U.S. patent application number 12/738066 was filed with the patent office on 2010-11-11 for novel compounds of reverse turn mimetics and the use thereof.
This patent application is currently assigned to Choongwae Pharma Corporation. Invention is credited to Jae Uk Chung, Min-Wook Jeong, Hee-Kyung Jung, Kyung-yun Jung, Hyun-Ju La.
Application Number | 20100286094 12/738066 |
Document ID | / |
Family ID | 43062707 |
Filed Date | 2010-11-11 |
United States Patent
Application |
20100286094 |
Kind Code |
A1 |
Chung; Jae Uk ; et
al. |
November 11, 2010 |
NOVEL COMPOUNDS OF REVERSE TURN MIMETICS AND THE USE THEREOF
Abstract
Conformationally constrained compounds that are novel and mimic
the secondary structure of reverse-turn regions of biologically
active peptides and proteins and having bicyclic framework are
disclosed, as well as their prodrugs. Such reverse-turn mimetic
structures and pro-drugs have utility over a wide range of fields,
including use as diagnostic and therapeutic agents. The invention
also relates to a use of such compounds for the preparation of a
medicament for treating or preventing cancer including an acute
myeloid leukemia.
Inventors: |
Chung; Jae Uk;
(Chungcheongbuk-do, KR) ; Jung; Kyung-yun;
(Gyeonggi-do, KR) ; Jeong; Min-Wook; (Gyeonggi-do,
KR) ; Jung; Hee-Kyung; (Gyeonggi-do, KR) ; La;
Hyun-Ju; (Gyeonggi-do, KR) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVE, SUITE 5400
SEATTLE
WA
98104
US
|
Assignee: |
Choongwae Pharma
Corporation
Seoul
KR
|
Family ID: |
43062707 |
Appl. No.: |
12/738066 |
Filed: |
October 15, 2008 |
PCT Filed: |
October 15, 2008 |
PCT NO: |
PCT/KR08/06070 |
371 Date: |
July 23, 2010 |
Related U.S. Patent Documents
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Application
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Patent Number |
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11974941 |
Oct 15, 2007 |
7671054 |
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12738066 |
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11108164 |
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7566711 |
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11974941 |
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10826972 |
Apr 16, 2004 |
7576084 |
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11108164 |
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10803179 |
Mar 17, 2004 |
7232822 |
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10826972 |
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10411877 |
Apr 9, 2003 |
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10803179 |
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10087443 |
Mar 1, 2002 |
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10411877 |
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10087443 |
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Current U.S.
Class: |
514/81 ;
514/233.2; 514/243; 544/112; 544/184 |
Current CPC
Class: |
A61P 35/02 20180101;
C07D 487/04 20130101; A61P 35/00 20180101 |
Class at
Publication: |
514/81 ; 544/184;
544/112; 514/243; 514/233.2 |
International
Class: |
A61K 31/53 20060101
A61K031/53; C07D 487/04 20060101 C07D487/04; A61K 31/5377 20060101
A61K031/5377; A61K 31/675 20060101 A61K031/675; A61P 35/02 20060101
A61P035/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 11, 2002 |
KR |
PCT/KR02/01901 |
Claims
1. A compound having a structure of Formula (I): ##STR00926## as an
isolated stereoisomer or a mixture of stereoisomers or as a
pharmaceutically acceptable salt thereof, wherein: E is
--ZR.sub.3-- or --(C.dbd.O)--, wherein Z is CH or N; W is
--(C.dbd.O)--, --(C.dbd.O)NH--, --(C.dbd.O)O--, --(C.dbd.O)S--,
--S(O).sub.2-- or a bond; R.sub.1 is: phenyl, substituted phenyl,
pyridinyl, substituted pyridinyl, pyrimidinyl, substituted
pyrimidinyl, indolyl, substituted indolyl, benzothiazolyl,
substituted benzothiazolyl, benzimidazolyl, substituted
benzimidazolyl, benzothiophenyl, substituted benzothiophenyl,
benzodioxolyl, substituted benzodioxolyl, benzoxazolyl, substituted
benzoxazolyl, benzisoxazolyl, substituted benzisoxazolyl,
chromonyl, substituted chromonyl, tetrahydro-carbazolyl,
substituted tetrahydro-carbazolyl, benzyl or substituted benzyl,
aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl; and each of R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 is the same or different and
independently an amino acid side chain moiety or an amino acid side
chain derivative.
2. The compound of claim 1, wherein: R.sub.1 is: substituted phenyl
having one or more substituents independently selected from:
halogen, nitro, cyano, hydroxyl, C.sub.1-12alkoxy, substituted
C.sub.1-12alkoxy, C.sub.1-12alkyl, carbonyl, carboxy, acetyl,
C.sub.1-12alkylthio, C.sub.6-12arylthio, thiophenyl, sulfonyl,
C.sub.6-12aryloxy, substituted C.sub.6-12aryloxy, indanyloxy,
amino, aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone,
phosphatemethyl, and imidazolyl; substituted pyridinyl having one
or more substituents independently selected from: halogen,
cycloalkyl, phenyl, substituted phenyl, pyrrolidinyl-piperidinyl,
pyridinyl, C.sub.1-12alkyl, carbonyl, amide, and carboxy;
substituted pyrimidinyl having one or more substituents
independently selected from phenyl and amino; substituted indolyl
having one or more substituents independently selected from:
phenyl, substituted phenyl, substituted benzyl, pyridinyl,
sulfonyl, acetyl, acyl, carbonyl, C.sub.1-12alkyl, acyloxy
C.sub.1-12alkyl, C.sub.1-12alkoxy, halogen, monoxide, and cyano;
substituted benzothiazolyl having one or more substituents
independently selected from: halogen, and phosphate disodium amino;
substituted benzimidazolyl having one or more substituents
independently selected from: carbonyl, monoxide, thio,
perfluoroC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, and C.sub.1-12alkyl;
substituted benzothiophenyl having one or more substituents
independently selected from: nitro, amino, C.sub.1-4alkylamino,
bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo,
aldoamino, and carbonyl; substituted benzodioxolyl having one or
more substituents independently selected from: nitro and halogen;
substituted benzoxazolyl having one or more substituents
independently selected from: monoxide, and thio; substituted
benzisoxazolyl having one or more substituents independently
selected from: amino; substituted chromonyl having one or more
substituents independently selected from: phenyl; or substituted
tetrahydro-carbazolyl having one or more substituents independently
selected from: sulfonyl.
3. The compound of claim 1 wherein R.sub.2, R.sub.4 and R.sub.5 are
independently selected from the group consisting of:
C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or more
substituents independently selected from: halogen, cyano,
C.sub.1-6alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, aminocarbonyl, morpholinyl,
methyl-piperazinyl, phenyl and hydroxyl; C.sub.2-12alkenyl or
substituted C.sub.2-12alkenyl having one or more substituents
independently selected from: amino, guanidino,
C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino, amidino,
C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.6-12aryl or substituted C.sub.6-12aryl having one or more
substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.1-6alkoxy; diC.sub.1-5alkylamino;
C.sub.6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur, or substituted
C.sub.6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur and has one or more substituents
independently selected from: halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, cyano, amino, amide, monoxide, thio, and hydroxyl;
and C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl having
one or more substituents independently selected from: amino,
amidino, amide, hydroxyC.sub.1-4alkyl, dihydroxyC.sub.1-4alkyl,
urea, thiourea, ureaC.sub.1-4alkyl, carbamoylurea, carbonyl,
carbonylamino, aminosulfo, amidesulfo, aminoC.sub.1-4alkyl,
acetylenyl, allyl, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4 dialkylamino, halogen, perfluoro C.sub.1-6alkyl,
C.sub.1-6alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
R.sub.3 is selected from the group consisting of: hydrogen;
C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or more
substituents independently selected from: halogen, cyano, C.sub.1-6
alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, and hydroxyl; C.sub.2-12alkenyl or
substituted C.sub.2-12alkenyl having one or more substituents
independently selected from: amino, guanidino,
C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino, amidino,
C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.6-12aryl or substituted C.sub.6-12aryl having one or more
substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.1-6alkoxy; C.sub.6-13heterocyclylalkyl, which has 1 to 2
heteroatoms selected from nitrogen, oxygen or sulfur, or
substituted C.sub.6-13heterocyclylalkyl which has 1 to 2
heteroatoms selected from nitrogen, oxygen or sulfur and has one or
more substituents independently selected from: halogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, and hydroxyl; and
C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl having one
or more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl.
4. The compound of claim 1, wherein R.sub.2, R.sub.4 and R.sub.5
are independently selected from the group consisting of:
aminoC.sub.2-5alkyl; guanidinoC.sub.2-5alkyl;
C.sub.1-4alkylguanidinoC.sub.2-5alkyl,
diC.sub.1-4alkylguanidino-C.sub.2-5alkyl; amidino C.sub.2-5alkyl;
C.sub.1-4alkylamidino C.sub.2-5alkyl;
diC.sub.1-4alkylamidinoC.sub.2-5alkyl; C.sub.1-3 alkoxy;
C.sub.1-12alkyl; C.sub.6-12aryl; C.sub.6-12arylalkyl;
C.sub.2-12alkenyl; phenyl or substituted phenyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4 dialkylamino,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3 alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl; naphthyl or
substituted naphthyl having one or more substituents independently
selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen,
perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro,
carboxy, cyano, sulfuryl, and hydroxyl; benzyl or substituted
benzyl having one or more substituents independently selected from:
amino, amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4 dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, C.sub.1-4alkyl, carbonyl,
aminoC.sub.1-4alkyl, acetylenyl, sulfuryl and hydroxyl;
bisphenylmethyl or substituted bisphenylmethyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; pyridinyl or substituted pyridinyl
having one or more substituents independently selected from: amino,
amide, monoxide, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl
and hydroxyl; pyridinylC.sub.1-4alkyl, or substituted
pyridinylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amide, monoxide, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4 dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3
alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyrimidinylC.sub.1-4alkyl, or substituted pyrimidinylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4
dialkylamino, halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, monoxide, amide,
and hydroxyl; triazin-2-ylC.sub.1-4alkyl, or substituted
triazin-2-ylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; imidazolylC.sub.1-4alkyl or
substituted imidazolylC.sub.1-4alkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3
alkoxy, nitro, carboxy, cyano, sulfuryl, monoxide and hydroxyl;
tetrazolylC.sub.1-4alkyl or substituted tetrazolylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
triazolylC.sub.1-4alkyl or substituted triazolylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
indolylC.sub.1-4alkyl or substituted indolylC.sub.1-4alkyl having
one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
indazolylC.sub.1-4alkyl or substituted indazolylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
benzoxazolylC.sub.1-4alkyl or substituted
benzoxazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
benzimidazolylC.sub.1-4alkyl or substituted
benzimidazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, thio, monoxide and hydroxyl;
benzotriazolylC.sub.1-4alkyl or substituted
benzotriazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
benzodioxolylC.sub.1-4alkyl, substituted
benzodioxolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
N-amidinopiperazinyl-N--C.sub.0-4alkyl,
N-amidinopiperidinylC.sub.1-4alkyl;
4-aminocyclohexylC.sub.0-2alkyl; thiophenylC.sub.1-4alkyl,
bipiperidinylcarbonyloxy; amideC.sub.1-4alkyl; ureaC.sub.1-4alkyl;
amino C.sub.1-4alkyl; cycloalkylC.sub.1-4alkyl and
diaminosulfurylC.sub.1-4alkyl; and R.sub.3 is selected from the
group consisting of: hydrogen; amino C.sub.2-5alkyl;
guanidinoC.sub.2-5alkyl; C.sub.1-4alkylguanidino C.sub.2-5alkyl,
diC.sub.1-4alkylguanidino-C.sub.2-5alkyl; amidino C.sub.2-5alkyl;
C.sub.1-4alkylamidino C.sub.2-5alkyl;
diC.sub.1-4alkylamidinoC.sub.2-5alkyl; C.sub.1-3alkoxy;
C.sub.1-12alkyl; C.sub.6-12aryl; C.sub.6-12arylalkyl;
C.sub.2-12alkenyl; phenyl or substituted phenyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4 dialkylamino,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3 alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl; naphthyl or
substituted naphthyl having one or more substituents independently
selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen,
perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro,
carboxy, cyano, sulfuryl, and hydroxyl; benzyl or substituted
benzyl having one or more substituents independently selected from:
amino, amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4 dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
bisphenylmethyl or substituted bisphenylmethyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; pyridinyl or substituted pyridinyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4
dialkylamino, halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyridinylC.sub.1-4alkyl, or substituted pyridinylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, sulfuryl
and hydroxyl; pyrimidinylC.sub.1-4alkyl, or substituted
pyrimidinylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; triazin-2-ylC.sub.1-4alkyl, or
substituted triazin-2-ylC.sub.1-4alkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3
alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
imidazolylC.sub.1-4alkyl or substituted imidazolylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-4alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, sulfuryl
and hydroxyl; N-amidinopiperazinyl-N--C.sub.0-4alkyl,
N-amidinopiperidinylC.sub.1-4alkyl; and
4-aminocyclohexylC.sub.0-2alkyl.
5. The compound of claim 2, wherein: substituted phenyl is
halo-phenyl, cyano phenyl, C.sub.1-12alkoxy phenyl, hydroxy phenyl,
carboxy phenyl, acetamide phenyl, aminocarbonyl phenyl, amino
phenyl, alkylsulfonyl phenyl, or alkylthio phenyl; substituted
benzyl is nitro-benzyl, or amino-benzyl; amide group is
C.sub.1-6alkylamide, carbamide, C.sub.1-6alkylcarbamide,
C.sub.1-6alkylcarbamate, C.sub.1-6alkylalkoxycarbamate, formamide,
C.sub.1-6alkylformamide, carbamoylurea, or acetamide; carbonyl
group is cycloalkylcarbonyl, C.sub.1-12alkoxycarbonyl,
morpholinylcarbonyl, aminocarbonyl, C.sub.1-12alkylaminocarbonyl,
di C.sub.1-12alkylaminocarbonyl, C.sub.1-12alkynylaminocarbonyl,
C.sub.2-13alkoxyalkylaminocarbonyl thiophenyl
C.sub.1-12alkylaminocarbonyl, benzylaminocarbonyl,
dihydropyrrolylcarbonyl, cycloalkyl C.sub.1-12alkylcarbonyl,
cycloalkenyl C.sub.1-12alkylcarbonyl,
C.sub.2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl,
piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl,
hydroxyaminocarbonyl, hydroC.sub.1-12alkylaminocarbonyl,
hydrazinylcarbonyl, C.sub.1-12alkylformatehydrazinylcarbonyl, or
tetrahydrofuranylC.sub.1-12alkylaminocarbonyl; sulfonyl group is
tosyl, phenyl sulfonyl, C.sub.1-12alkyl sulfonyl,
C.sub.1-12alkylsulfonylamino, aminosulfonylamino or halo-phenyl
sulfonyl; substituted alkoxy is morpholinyl C.sub.1-12alkoxy,
dihalo-C.sub.1-12alkoxy, or piperazinyl C.sub.1-12alkoxy;
substituted aryloxy is halo-C.sub.6-12aryloxy; substituted
pyridinyl is halo-pyridinyl, C.sub.1-12alkoxy pyridinyl, amino
pyridinyl, or morpholinyl pyridinyl; or substituted
tetrahydro-carbazolyl is
phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
6. The compound of claim 1 wherein R.sub.2, R.sub.4 and R.sub.5 are
independently selected from the group consisting of:
C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or more
substituents independently selected from acyl, carboxy, alkylthio,
aminocarbonyl, morpholinyl, methyl-piperazinyl, phenyl, cyano,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, hydroxyl,
C.sub.1-6alkoxy, and phenylsulfonyl; C.sub.2-12alkenyl or
substituted C.sub.2-12alkenyl having one or more substituents
independently selected from acyl, carboxy, alkylthio, and
phenylsulfonyl; substituted C.sub.6-12aryl substituted with
amidosulfonate; arylC.sub.1-4alkyl or substituted
arylC.sub.1-4alkyl having one or more substituents independently
selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, C.sub.3-6cycloalkyl,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-6alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl, hydroxyl,
C.sub.1-6alkyloxyC.sub.1-6acyl, morphorlinylC.sub.1-6alkyl, aryl,
aryloxy, (alkyl)(arylalkyl)amino, heterocyclyl, acyl,
amidosulfonate, aminocarbonyl, alkylsulfonate, alkylsulfonyl,
alkylthio, arylthio, phenylsulfonate, phenylsulfonyl,
morphorlinylC.sub.1-3alkoxy, N-formamidyl, amide,
hydroxyC.sub.1-4alkyl, dihydroxyC.sub.1-4alkyl, urea, thiourea,
ureaC.sub.1-4alkyl, carbamoylurea, carbonyl, carbonylamino,
aminosulfo, amidesulfo, aminoC.sub.1-4alkyl, allyl, acetylenyl, and
pyrrolidonyl; heterocyclyl or substituted heterocyclyl having one
or more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4 dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-6alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl;
heterocyclylC.sub.1-4alkyl or substituted
heterocyclylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amide, monoxide, thio, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
C.sub.3-6cycloalkyl, halogen, perfluoroC.sub.1-4alkyl,
C.sub.1-6alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, sulfuryl,
hydroxyl, C.sub.1-6alkyloxyC.sub.1-6 acyl,
morphorlinylC.sub.1-6alkyl, arylalkyl, aryl, heterocyclyl, acyl,
phenylsulfonyl, cycloalkylalkyl, acyloxyalkyl, aminocarbonyl, and
C.sub.1-4alkylformamidyl; cycloalkyl or substituted cycloalkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4
dialkylamino, halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
cycloalkylalkyl or substituted cycloalkylalkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3
alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and R.sub.3
is selected from the group consisting of: hydrogen; C.sub.1-12alkyl
or substituted C.sub.1-12alkyl having one or more substituents
independently selected from acyl, carboxy, alkylthio, and
phenylsulfonyl; C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl
having one or more substituents independently selected from acyl,
carboxy, alkylthio, and phenylsulfonyl; substituted C.sub.6-12aryl
substituted with amidosulfonate; arylC.sub.1-4alkyl or substituted
arylC.sub.1-4alkyl having one or more substituents independently
selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, C.sub.3-6cycloalkyl,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-6alkyl, C.sub.1-3 alkoxy,
nitro, carboxy, cyano, sulfuryl, hydroxyl,
C.sub.1-6alkyloxyC.sub.1-6acyl, morphorlinylC.sub.1-6alkyl, aryl,
aryloxy, (alkyl)(arylalkyl)amino, heterocyclyl, acyl,
amidosulfonate, aminocarbonyl, alkylsulfonate, alkylsulfonyl,
alkylthio, arylthio, phenylsulfonate, phenylsulfonyl,
morphorlinylC.sub.1-3alkoxy, N-formamidyl, and pyrrolidonyl;
heterocyclyl or substituted heterocyclyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4 dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; heterocyclylC.sub.1-4alkyl or
substituted heterocyclylC.sub.1-4alkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4 dialkylamino,
C.sub.3-6 cycloalkyl, halogen, perfluoroC.sub.1-4alkyl,
C.sub.1-6alkyl, C.sub.1-3 alkoxy, nitro, carboxy, cyano, sulfuryl,
hydroxyl, C.sub.1-6alkyloxyC.sub.1-6acyl,
morphorlinylC.sub.1-6alkyl, arylalkyl, aryl, heterocyclyl, acyl,
phenylsulfonyl, cycloalkylalkyl, acyloxyalkyl, aminocarbonyl and
C.sub.1-4alkylformamidyl; cycloalkyl or substituted cycloalkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4
dialkylamino, halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl; and
cycloalkylalkyl or substituted cycloalkylalkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3
alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl.
7. The compound of claim 6, wherein: arylC.sub.1-4alkyl is benzyl,
bisphenylmethyl, naphthylmethyl or 3,3-bisphenylpropyl; and
heterocyclylC.sub.1-4alkyl is benzotriazolylC.sub.1-4alkyl,
benzopyrazolylC.sub.1-4alkyl, indazolylC.sub.1-4alkyl,
isoquinolylC.sub.1-4alkyl, benzothiazolylC.sub.1-4alkyl,
quinolinylC.sub.1-4alkyl, imidazolinylC.sub.1-4alkyl,
thienylC.sub.1-4alkyl, tetrahydro furanylC.sub.1-4alkyl,
pyridinylC.sub.1-4alkyl, pyrimidinylC.sub.1-4alkyl,
benzimidazolylC.sub.1-4alkyl, thiophenylC.sub.1-4alkyl,
triazolylC.sub.1-4alkyl, tetrazolylC.sub.1-4alkyl,
benzoxazolylC.sub.1-4alkyl, benzodioxolylC.sub.1-4alkyl or
indolylC.sub.1-4alkyl.
8. The compound of claim 1 wherein E is CHR.sub.3 and the compound
has a structure of Formula (II): ##STR00927## wherein: W is
--(C.dbd.O)--, --(C.dbd.O)NH--, --(C.dbd.O)O--, --(C.dbd.O)S--,
--S(O).sub.2-- or a bond; R.sub.1 is: phenyl, substituted phenyl,
pyridinyl, substituted pyridinyl, pyrimidinyl, substituted
pyrimidinyl, indolyl, substituted indolyl, benzothiazolyl,
substituted benzothiazolyl, benzimidazolyl, substituted
benzimidazolyl, benzothiophenyl, substituted benzothiophenyl,
benzodioxolyl, substituted benzodioxolyl, benzoxazolyl, substituted
benzoxazolyl, benzisoxazolyl, substituted benzisoxazolyl,
chromonyl, substituted chromonyl, tetrahydro-carbazolyl,
substituted tetrahydro-carbazolyl, benzyl or substituted benzyl,
aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl; R.sub.2, R.sub.4 and
R.sub.5 are independently selected from the group consisting of:
C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or more
substituents independently selected from: halogen, cyano, C.sub.1-6
alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, aminocarbonyl, morpholinyl,
methyl-piperazinyl, phenyl and hydroxyl; C.sub.2-12alkenyl or
substituted C.sub.2-12alkenyl having one or more substituents
independently selected from: amino, guanidino,
C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino, amidino,
C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.6-12aryl or substituted C.sub.6-12aryl having one or more
substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-4alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.1-6alkoxy; diC.sub.1-5alkylamino;
C.sub.6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur, or substituted
C.sub.6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur and has one or more substituents
independently selected from: halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, cyano, and hydroxyl; and C.sub.7-13arylalkyl or
substituted C.sub.7-13arylalkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, carboxy, cyano, sulfuryl,
acetylenyl, hydroxyl, phosphate, dimethylaminoacetate,
dimethylaminoalkylcarbamate, and diethyl-phosphono-acetamido; and
R.sub.3 is selected from the group consisting of: hydrogen;
C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or more
substituents independently selected from: halogen, cyano, C.sub.1-6
alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, and hydroxyl; C.sub.2-12alkenyl or
substituted C.sub.2-12alkenyl having one or more substituents
independently selected from: amino, guanidino,
C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino, amidino,
C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.6-12aryl or substituted C.sub.6-12aryl having one or more
substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
C.sub.1-6alkoxy; C.sub.6-13heterocyclylalkyl, which has 1 to 2
heteroatoms selected from nitrogen, oxygen or sulfur, or
substituted C.sub.6-13heterocyclylalkyl which has 1 to 2
heteroatoms selected from nitrogen, oxygen or sulfur and has one or
more substituents independently selected from: halogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, and hydroxyl; and
C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl having one
or more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl.
9. The compound of claim 8, wherein R.sub.1 is: substituted phenyl
having one or more substituents independently selected from:
halogen, nitro, cyano, hydroxyl, C.sub.1-12alkoxy, substituted
C.sub.1-12alkoxy, C.sub.1-12alkyl, carbonyl, carboxy, acetyl,
C.sub.1-12alkylthio, C.sub.6-12arylthio, thiophenyl, sulfonyl,
C.sub.6-12aryloxy, substituted C.sub.6-12aryloxy, indanyloxy,
amino, aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and
imidazolyl; substituted pyridinyl having one or more substituents
independently selected from: halogen, cycloalkyl, phenyl,
substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl,
C.sub.1-12alkyl, carbonyl, amide, and carboxy; substituted
pyrimidinyl having one or more substituents independently selected
from phenyl and amino; substituted indolyl having one or more
substituents independently selected from: phenyl, substituted
phenyl, substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl,
carbonyl, C.sub.1-12alkyl, acyloxy C.sub.1-12alkyl,
C.sub.1-12alkoxy, halogen, monoxide, and cyano; substituted
benzimidazolyl having one or more substituents independently
selected from: carbonyl, monoxide, thio, perfluoroC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, and C.sub.1-12alkyl; substituted
benzothiophenyl having one or more substituents independently
selected from: nitro, amino, C.sub.1-4alkylamino, bisbenzylamino,
amide, halogen, benzylamino, sulfonyl, dioxo, aldoamino, and
carbonyl; substituted benzodioxolyl having one or more substituents
independently selected from: nitro and halogen; substituted
benzoxazolyl having one or more substituents independently selected
from: monoxide, and thio; substituted benzisoxazolyl having one or
more substituents independently selected from: amino; substituted
chromonyl having one or more substituents independently selected
from: phenyl; or substituted tetrahydro-carbazolyl having one or
more substituents independently selected from: sulfonyl; R.sub.2
and R.sub.5 is independently C.sub.1-12alkyl, C.sub.6-12aryl,
C.sub.7-12arylalkyl, C.sub.6-11heterocyclylalkyl, hydroxybenzyl, or
substituted benzyl having a substituents selected from phosphate,
dimethylaminoacetate, (2-dimethylamino-ethyl)-carbamate, and
diethyl-phosphono-acetamido; R.sub.3 is hydrogen or
C.sub.1-12alkyl; and R.sub.4 is C.sub.1-12alkyl,
C.sub.7-12arylalkyl, or C.sub.2-12alkenyl.
10. The compound of claim 9, wherein: substituted phenyl is
halo-phenyl, cyano phenyl, C.sub.1-12alkoxy phenyl, hydroxy phenyl,
carboxy phenyl, acetamide phenyl, aminocarbonyl phenyl, amino
phenyl, alkylsulfonyl phenyl, or alkylthio phenyl; substituted
benzyl is nitro-benzyl, or amino-benzyl; amide group is
C.sub.1-6alkylamide, carbamide, C.sub.1-6alkylcarbamide,
C.sub.1-6alkylcarbamate, C.sub.1-6alkylalkoxycarbamate, formamide,
C.sub.1-6alkylformamide, carbamoylurea, or acetamide; carbonyl
group is cycloalkylcarbonyl, C.sub.1-12alkoxycarbonyl,
morpholinylcarbonyl, aminocarbonyl, C.sub.1-12alkylaminocarbonyl,
di C.sub.1-12alkylaminocarbonyl, C.sub.1-12alkynylaminocarbonyl,
C.sub.2-13alkoxyalkylaminocarbonyl thiophenyl
C.sub.1-12alkylaminocarbonyl, benzylaminocarbonyl,
dihydropyrrolylcarbonyl, cycloalkyl C.sub.1-12alkylcarbonyl,
cycloalkenyl C.sub.1-12alkylcarbonyl,
C.sub.2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl,
piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl,
hydroxyaminocarbonyl, hydroC.sub.1-12alkylaminocarbonyl,
hydrazinylcarbonyl, C.sub.1-12alkylformatehydrazinylcarbonyl, or
tetrahydrofuranylC.sub.1-12alkylaminocarbonyl; sulfonyl group is
tosyl, phenyl sulfonyl, C.sub.1-12alkyl sulfonyl,
C.sub.1-12alkylsulfonylamino, aminosulfonylamino or halo-phenyl
sulfonyl; substituted alkoxy is morpholinyl C.sub.1-12alkoxy,
dihalo-C.sub.1-12alkoxy, or piperazinyl C.sub.1-12alkoxy;
substituted aryloxy is halo-C.sub.6-12aryloxy; substituted
pyridinyl is halo-pyridinyl, C.sub.1-12alkoxy pyridinyl, amino
pyridinyl, or morpholinyl pyridinyl; or substituted
tetrahydro-carbazolyl is
phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
11. The compound of claim 8 wherein the compound has the structure
of Formula (III): ##STR00928## wherein: R.sub.1 is phenyl,
substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl,
substituted pyrimidinyl, indolyl, substituted indolyl,
benzothiazolyl, substituted benzothiazolyl, benzimidazolyl,
substituted benzimidazolyl, benzothiophenyl, substituted
benzothiophenyl, benzodioxolyl, substituted benzodioxolyl,
benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted
benzisoxazolyl, chromonyl, substituted chromonyl,
tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or
substituted benzyl, aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl; R.sub.6 is C.sub.6-12aryl
or substituted C.sub.6-12aryl having one or more substituents
independently selected from the group consisting of: halogen;
hydroxyl; cyano; C.sub.1-6alkyl; and C.sub.1-6alkoxy; or
C.sub.5-12heterocyclyl or substituted C.sub.5-12heterocyclyl having
one or more substituents independently selected from: halogen,
hydroxyl, cyano, C.sub.1-6alkyl, and C.sub.1-6alkoxy; R.sub.4 is
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl or
perfluoroC.sub.1-6alkyl; X.sub.1 is hydrogen, hydroxyl or halogen;
and each of X.sub.2 and X.sub.3 is independently hydrogen,
hydroxyl, phosphate, dimethylaminoacetate,
(2-dimethylamino-ethyl)-carbamate, diethyl-phosphono-acetamido or
halogen.
12. The compound of claim 11 wherein: R.sub.1 is substituted phenyl
having one or more substituents independently selected from:
halogen, nitro, cyano, hydroxyl, C.sub.1-12alkoxy, substituted
C.sub.1-12alkoxy, C.sub.1-12alkyl, carbonyl, carboxy, acetyl,
C.sub.1-12alkylthio, C.sub.6-12arylthio, thiophenyl, sulfonyl,
C.sub.6-12aryloxy, substituted C.sub.6-12aryloxy, indanyloxy,
amino, aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and
imidazolyl; substituted pyridinyl having one or more substituents
independently selected from: halogen, cycloalkyl, phenyl,
substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl,
C.sub.1-12alkyl, carbonyl, amide, and carboxy; substituted
pyrimidinyl having one or more substituents independently selected
from phenyl and amino: substituted indolyl having one or more
substituents independently selected from: phenyl, substituted
phenyl, substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl,
carbonyl, C.sub.1-12alkyl, acyloxy C.sub.1-12alkyl,
C.sub.1-12alkoxy, halogen, monoxide, and cyano; substituted
benzimidazolyl having one or more substituents independently
selected from: carbonyl, monoxide, thio, perfluoroC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, and C.sub.1-12alkyl; substituted
benzothiophenyl having one or more substituents independently
selected from: nitro, amino, C.sub.1-4alkylamino, bisbenzylamino,
amide, halogen, benzylamino, sulfonyl, dioxo, aldoamino, and
carbonyl; substituted benzodioxolyl having one or more substituents
independently selected from: nitro and halogen; substituted
benzoxazolyl having one or more substituents independently selected
from: monoxide, and thio; substituted benzisoxazolyl having one or
more substituents independently selected from: amino; substituted
chromonyl having one or more substituents independently selected
from: phenyl; or substituted tetrahydro-carbazolyl having one or
more substituents independently selected from: sulfonyl; R.sub.4 is
C.sub.1-3alkyl or allyl; and R.sub.6 is phenyl or substituted
phenyl having one or more substituents independently selected from:
halogen, hydroxyl, cyano, C.sub.1-6alkyl and C.sub.1-6alkoxy; or
pyridyl or substituted pyridyl having one or more substituents
independently selected from: halogen, hydroxyl, cyano,
C.sub.1-6alkyl and C.sub.1-6alkoxy.
13. The compound of claim 12, wherein: substituted phenyl is
halo-phenyl, cyano phenyl, C.sub.1-12alkoxy phenyl, hydroxy phenyl,
carboxy phenyl, acetamide phenyl, aminocarbonyl phenyl, amino
phenyl, alkylsulfonyl phenyl, or alkylthio phenyl; substituted
benzyl is nitro-benzyl, or amino-benzyl; amide group is
C.sub.1-6alkylamide, carbamide, C.sub.1-6alkylcarbamide,
C.sub.1-6alkylcarbamate, C.sub.1-6alkylalkoxycarbamate, formamide,
C.sub.1-6alkylformamide, carbamoylurea, or acetamide; carbonyl
group is cycloalkylcarbonyl, C.sub.1-12alkoxycarbonyl,
morpholinylcarbonyl, aminocarbonyl, C.sub.1-12alkylaminocarbonyl,
di C.sub.1-12alkylaminocarbonyl, C.sub.1-12alkynylaminocarbonyl,
C.sub.2-13alkoxyalkylaminocarbonyl thiophenyl
C.sub.1-12alkylaminocarbonyl, benzylaminocarbonyl,
dihydropyrrolylcarbonyl, cycloalkyl C.sub.1-12alkylcarbonyl,
cycloalkenyl C.sub.1-12alkylcarbonyl,
C.sub.2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl,
piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl,
hydroxyaminocarbonyl, hydroC.sub.1-12alkylaminocarbonyl,
hydrazinylcarbonyl, C.sub.1-12alkylformatehydrazinylcarbonyl, or
tetrahydrofuranylC.sub.1-12alkylaminocarbonyl; sulfonyl group is
tosyl, phenyl sulfonyl, C.sub.1-12alkyl sulfonyl,
C.sub.1-12alkylsulfonylamino, aminosulfonylamino or halo-phenyl
sulfonyl; substituted alkoxy is morpholinyl C.sub.1-12alkoxy,
dihalo-C.sub.1-12alkoxy, or piperazinyl C.sub.1-12alkoxy;
substituted aryloxy is halo-C.sub.6-12aryloxy; substituted
pyridinyl is halo-pyridinyl, C.sub.1-12alkoxy pyridinyl, amino
pyridinyl, or morpholinyl pyridinyl; substituted
tetrahydro-carbazolyl is
phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
14. A compound having a structure of Formula (IV): (III)-R.sub.7
(IV) wherein (III) is: ##STR00929## and one of R.sub.1, R.sub.4,
R.sub.6, X.sub.1, X.sub.2, and X.sub.3 is linked to R.sub.7 via Y,
wherein Y is an oxygen, sulfur, or nitrogen in R.sub.1, R.sub.4, or
R.sub.6, or an oxygen in X.sub.i1l , X.sub.2, or X.sub.3, and
R.sub.7 is hydroxyalkyl, glycosyl, phosphoryloxymethyloxycarbonyl,
substituted or unsubstituted piperidine carbonyloxy, or a salt
thereof; or Y--R.sub.7 is an amino acid residue, a combination of
amino acid residues, phosphate, hemimalate, hemisuccinate,
dimethylaminoalkylcarbamate, dimethylaminoacetate, or a salt
thereof; and when not linked to R.sub.7, R.sub.1 is phenyl,
substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl,
substituted pyrimidinyl, indolyl, substituted indolyl,
benzothiazolyl, substituted benzothiazolyl, benzimidazolyl,
substituted benzimidazolyl, benzothiophenyl, substituted
benzothiophenyl, benzodioxolyl, substituted benzodioxolyl,
benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted
benzisoxazolyl, chromonyl, substituted chromonyl,
tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or
substituted benzyl, aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl; R.sub.6 is C.sub.6-12aryl
or substituted C.sub.6-12aryl having one or more substituents
independently selected from the group consisting of: halogen;
hydroxyl; cyano; C.sub.1-6alkyl; and C.sub.1-6alkoxy; or
C.sub.5-12heterocyclyl or substituted C.sub.5-12heterocyclyl having
one or more substituents independently selected from: halogen,
hydroxyl, cyano, C.sub.1-6alkyl, and C.sub.1-6alkoxy; R.sub.4 is
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl or
perfluoroC.sub.1-6alkyl; and each of X.sub.1, X.sub.2 and X.sub.3
is independently hydrogen, hydroxyl or halogen.
15. The compound of claim 14 wherein R.sub.1 is: substituted phenyl
having one or more substituents independently selected from:
halogen, nitro, cyano, hydroxyl, C.sub.1-12alkoxy, substituted
C.sub.1-12alkoxy, C.sub.1-12alkyl, carbonyl, carboxy, acetyl,
C.sub.1-12alkylthio, C.sub.6-12arylthio, thiophenyl, sulfonyl,
C.sub.6-12aryloxy, substituted C.sub.6-12aryloxy, indanyloxy,
amino, aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and
imidazolyl; substituted pyridinyl having one or more substituents
independently selected from: halogen, cycloalkyl, phenyl,
substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl,
C.sub.1-12alkyl, carbonyl, amide, and carboxy; substituted
pyrimidinyl having one or more substituents independently selected
from phenyl and amino; substituted indolyl having one or more
substituents independently selected from: phenyl, substituted
phenyl, substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl,
carbonyl, C.sub.1-12alkyl, acyloxy C.sub.1-12alkyl,
C.sub.1-12alkoxy, halogen, monoxide, and cyano; substituted
benzimidazolyl having one or more substituents independently
selected from: carbonyl, monoxide, thio, perfluoroC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, and C.sub.1-12alkyl; substituted
benzothiophenyl having one or more substituents independently
selected from: nitro, amino, C.sub.1-4alkylamino, bisbenzylamino,
amide, halogen, benzylamino, sulfonyl, dioxo, aldoamino, and
carbonyl; substituted benzodioxolyl having one or more substituents
independently selected from: nitro and halogen; substituted
benzoxazolyl having one or more substituents independently selected
from: monoxide, and thio; substituted benzisoxazolyl having one or
more substituents independently selected from: amino; substituted
chromonyl having one or more substituents independently selected
from: phenyl; or substituted tetrahydro-carbazolyl having one or
more substituents independently selected from: sulfonyl; R.sub.4 is
C.sub.1-3alkyl or allyl; and R.sub.6 is phenyl or substituted
phenyl having one or more substituents independently selected from:
halogen, hydroxyl, cyano, C.sub.1-6alkyl and C.sub.1-6alkoxy; or
pyridyl or substituted pyridyl having one or more substituents
independently selected from: halogen, hydroxyl, cyano,
C.sub.1-6alkyl and C.sub.1-6alkoxy.
16. A method for treating or preventing an acute myeloid leukemia,
comprising administering to a patient in need thereof an effective
amount of the compound according to claim 1.
Description
TECHNICAL FIELD
[0001] The present invention relates generally to novel compounds
of reverse-turn mimetics and their application in the treatment of
medical conditions, e.g., cancer diseases, and pharmaceutical
compositions comprising the mimetics.
BACKGROUND ART
[0002] Random screening of molecules for possible activity as
therapeutic agents has occurred for many years and resulted in a
number of important drug discoveries. While advances in molecular
biology and computational chemistry have led to increased interest
in what has been termed "rational drug design," such techniques
have not proven as fast or reliable as initially predicted. Thus,
in recent years there has been a renewed interest and return to
random drug screening. To this end, particular strides having been
made in new technologies based on the development of combinatorial
chemistry libraries, and the screening of such libraries in search
for biologically active members.
[0003] Initially, combinatorial chemistry libraries were generally
limited to members of peptide or nucleotide origin.
[0004] While combinatorial libraries containing members of peptide
and nucleotide origin are of significant value, there is still a
need in the art for libraries containing members of different
origin. For example, traditional peptide libraries to a large
extent merely vary the amino acid sequence to generate library
members. While it is well recognized that the secondary structures
of peptides are important to biological activity, such peptide
libraries do not impart a constrained secondary structure to its
library members.
[0005] To this end, some researchers have cyclized peptides with
disulfide bridges in an attempt to provide a more constrained
secondary structure (Tumelty et al., J. Chem. Soc. 1067-68, 1994;
Eichler et al., Peptide Res. 7:300-306, 1994). However, such
cyclized peptides are generally still quite flexible and are poorly
bioavailable, and thus have met with only limited success.
[0006] More recently, non-peptide compounds have been developed
which more closely mimic the secondary structure of reverse-turns
found in biologically active proteins or peptides. For example,
U.S. Pat. No. 5,440,013 to Kahn and published PCT Applications Nos.
WO94/03494, WO01/00210A1, and WO01/16135A2 to Kahn each disclose
conformationally constrained, non-peptidic compounds, which mimic
the three-dimensional structure of reverse-turns. In addition, U.S.
Pat. No. 5,929,237 and its continuation-in-part U.S. Pat. No.
6,013,458, both to Kahn, disclose conformationally constrained
compounds which mimic the secondary structure of reverse-turn
regions of biologically active peptides and proteins. The synthesis
and identification of conformationally constrained, reverse-turn
mimetics and their application to diseases were well reviewed by
Obrecht (Advances in Med. Chem., 4, 1-68, 1999).
[0007] While significant advances have been made in the synthesis
and identification of conformationally constrained, reverse-turn
mimetics, there remains a need in the art for small molecules which
mimic the secondary structure of peptides. There is also a need in
the art for libraries containing such members, as well as
techniques for synthesizing and screening the library members
against targets of interest, particularly biological targets, to
identify bioactive library members.
[0008] In the mean time, a proto-oncogene is a normal gene that can
become an oncogene due to mutations or increased expression. c-Myc
(MYC) is known as one of the proto-oncogenes, and dysregulation of
c-Myc is considered one of a series of oncogenic events required
for mammalian tumorigenesis (Pelengaris S, Khan M. The many faces
of c-MYC. Arch Biochem Biophys. 2003; 416:129-136). MYC
dysregulation, via a variety of mechanisms, was also found to be
associated with myeloid leukemias (Hoffman B, Amanullah A,
Shafarenko M, Liebermann D A. The proto-oncogene c-myc in
hematopoietic development and leukemogenesis. Oncogene. 2002; 21:
3414-3421). In addition, c-Myc was found to rapidly induce acute
myeloid leukemia (Hui Luo et al. "c-Myc rapidly induces acute
myeloid leukemia in mice without evidence of lymphoma-associated
antiapoptotic mutations," Blood, 1 Oct. 2005, volume 106, Number 7,
pp 2452.about.2461).
[0009] As c-Myc can be upregulated in acute myeloid leukemia, the
oncogenic function of c-Myc has been studied and its exact role in
myeloid leukemogenesis has been studied. Recently, some scientist
found that Myc preferentially stimulated the growth of myeloid
progenitor cells in methylcellulose and showed that Myc is a
critical downstream effector of myeloid leukemogenesis (ibid.).
[0010] The finding that c-Myc plays a critical role in myeloid
leukemogenesis indicates that by inhibiting an activation of c-Myc
protein, an acute myeloid leukemia can be cured or prevented.
[0011] On the other hand, enzymes of the cytochrome P450 (CYP)
superfamily are the major determinants of half-life and execute
pharmacological effects of many therapeutic drugs. The human
cytochrome P450 (CYP) 3A subfamily, includes CYP3A4, which is most
abundant in the human liver (.about.40%) and metabolizes more than
50% of clinically used drugs (Shimada et al 1994; Rendic and Di
Carlo 1997).
Due to the key role of CYP3A4 in drug metabolism, significant
inactivation of this enzyme could result in marked pharmacokinetic
drug-drug interactions. Inhibition of CYP3A4 may cause severe drug
toxicity through the enhanced exposure to coadministered drugs
(Dresser et al 2000). For example, when irreversible CYP3A4
inhibitors such as erythromycin or clarithromycin are
coadministered with terfenadine, astemizole, or pimozide patients
may experience Torsades de pointes (a life-threatening ventricular
arrhythmia associated with QT prolongation) (Spinier et al 1995;
Dresser et al 2000). Cancer patients, at times, undergo multiple
treatment regimes, which increases the risk of drug-drug
interactions followed by adverse drug reactions.
[0012] Therefore, in developing therapeutic agents, especially when
it is to be administered in combination with other drugs, there is
a need for providing compounds having less CYP3A4 inhibitory
activity.
DISCLOSURE OF INVENTION
Technical Problem
[0013] The object of the present invention is to provide novel
compounds which mimic the secondary structure of reverse-turn
regions of biologically active peptides and proteins and have
biological activity such as anti-cancer effect.
[0014] Another object of the present invention is to provide novel
compounds which inhibit Wnt signaling.
[0015] Yet another object of the present invention is to provide
novel compounds which can be used as pharmaceuticals, in particular
having less CYP3A4 inhibitory activity (higher IC50).
[0016] Yet another object of the present invention is to provide
novel compounds for a treatment or a prevention of acute myeloid
leukemia.
Technical Solution
[0017] The present invention is directed to a new type of
conformationally constrained compounds and derivatives including
prodrugs thereof, which mimic the secondary structure of
reverse-turn regions of biologically active peptides and proteins.
This invention also discloses libraries containing such compounds,
as well as the synthesis and screening thereof.
[0018] The compounds of the present invention have the following
general Formula (I):
##STR00001##
wherein E is --ZR.sub.3-- or --(C.dbd.O)--, wherein Z is CH or N; W
is --(C.dbd.O)--, --(C.dbd.O)NH--, --(C.dbd.O)O--, --(C.dbd.O)S--,
--S(O).sub.2-- or a bond; and each of R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is the same or different and independently an
amino acid side chain moiety or an amino acid side chain
derivative. The reverse turn mimetic compound may be present as an
isolated stereoisomer or a mixture of stereoisomers or as a
pharmaceutically acceptable salt thereof.
[0019] In certain embodiments, R.sub.1 of compounds of Formula (I)
is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl,
pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl,
benzothiazolyl, substituted benzothiazolyl, benzimidazolyl,
substituted benzimidazolyl, benzothiophenyl, substituted
benzothiophenyl, benzodioxolyl, substituted benzodioxolyl,
benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted
benzisoxazolyl, chromonyl, substituted chromonyl,
tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or
substituted benzyl, aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl.
[0020] Specific examples of R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are provided in the following detailed description.
[0021] In an embodiment wherein E is CHR.sub.3, the compounds of
this invention have the following Formula (II):
##STR00002##
wherein W is as defined above, and R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 are as defined in the following detailed
description.
[0022] In certain embodiments, the compounds of this invention have
the following general Formula (III):
##STR00003##
wherein R.sub.1, R.sub.4, R.sub.6, X.sub.1, X.sub.2, and X.sub.3
are defined in the following detailed description.
[0023] The present invention is also related to prodrugs using the
libraries containing one or more compounds of Formula (I). A
prodrug is typically designed to release the active drug in the
body during or after absorption by enzymatic and/or chemical
hydrolysis. The prodrug approach is an effective means of improving
the oral bioavailability or i.v. administration of poorly
water-soluble drugs by chemical derivatization to more
water-soluble compounds. The most commonly used prodrug approach
for increasing aqueous solubility of drugs containing a hydroxyl
group is to produce esters containing an ionizable group; e.g.,
phosphate group, carboxylate group, alkylamino group (Fleisher et
al., Advanced Drug Delivery Reviews, 115-130, 1996; Davis et al.,
Cancer Res., 7247-7253, 2002, Golik et al., Bioorg. Med. Chem.
Lett., 1837-1842, 1996).
Examples of the functional group which may be released in the body
may include phosphate,
##STR00004##
but any other functional groups that are conventionally used as the
ionizable group in a prodrug can be used.
[0024] In certain embodiments, the prodrugs of the present
invention have the following general Formula (IV):
(III)-R.sub.7 (IV)
wherein (III) is Formula (III) as described above; one of R.sub.1,
R.sub.4, R.sub.6, X.sub.1, X.sub.2, and X.sub.3 is linked to
R.sub.7 via Y; Y is an oxygen, sulfur, or nitrogen in R.sub.1,
R.sub.4, or R.sub.6, or an oxygen in X.sub.1, X.sub.2, or X.sub.3;
and R.sub.7 is hydroxyalkyl, glycosyl,
phosphoryloxymethyloxycarbonyl, substituted or unsubstituted
piperidine carbonyloxy, or a salt thereof; or Y--R.sub.7 is an
amino acid residue, a combination of amino acid residues,
phosphate, hemimalate, hemisuccinate, dimethylaminoalkylcarbamate,
dimethylaminoacetate, or a salt thereof; and when not linked to
R.sub.7: R.sub.1, R.sub.4, R.sub.6, X.sub.1, X.sub.2, and X.sub.3
are defined in the following detailed description.
[0025] In certain embodiments, the prodrugs of the present
invention are capable of serving as a substrate for a phosphatase,
a carboxylase, or other enzymes and are thereby converted to
compounds having general Formula (III). The present invention is
also directed to libraries containing one or more compounds of
Formula (I) above, as well as methods for synthesizing such
libraries and methods for screening the same to identify
biologically active compounds.
[0026] In a related aspect, the present invention further provides
novel compounds which have less CYP3A4 inhibitory activity. The
present invention also provides novel compounds which have
inhibition activity against Wnt signaling. The present invention
also provides novel compounds which can be used for the preparation
of a medicament for a treatment or a prevention of acute myeloid
leukemia.
ADVANTAGEOUS EFFECTS
[0027] The present invention provides novel compounds of
reverse-turn mimetics. The compounds of the present invention
exhibit less CYP3A4 inhibitory activity (higher IC50) which allows
the compounds as potential pharmaceuticals, especially when it is
to be administered in combination with other drugs. The compounds
of the present invention showed strong inhibition activity against
Wnt signaling. The compounds inhibited the growth of AML cancer
cells and it can be used in the treatment or prevention of an acute
myeloid leukemia.
BRIEF DESCRIPTION OF THE DRAWING
[0028] Reference will now be made in detail to the preferred
embodiment of the present invention, examples of which are
illustrated in the drawings attached herein. The embodiments are
described below so as to explain the present invention by referring
to the figures.
[0029] FIG. 1 provides a general synthetic scheme for preparing
revers-turn mimetics of the present invention.
[0030] FIGS. 2A to 2E show an effect of test compounds (Compounds
A.about.E) on the CYP3A4 activity. The graph is based on the
measurement of IC.sub.50 for Compounds A.about.E of the present
invention of CYP3A4 inhibition assay, wherein inhibition of
activity of CYP3A4 was measured at various concentrations of the
compound to obtain the IC50 value. Detailed procedures are
disclosed in Example 1.
[0031] FIG. 3 shows the results of the measurement of IC.sub.50 of
Compound F for SW480 cells on TopFlash Reporter Gene Bioassay.
[0032] FIG. 4 shows inhibition of growth of AML cancer cells by the
test compound according to the concentration of the test compound
(Compound B).
BEST MODE FOR CARRYING OUT THE INVENTION
[0033] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0034] "Amino" refers to the --NH.sub.2 radical.
[0035] "Amidino" refers to the --C(.dbd.NH)--NH.sub.2 radical. One
or both hydrogens of the amine group of the amidino may be replaced
with one or two alkyl groups, as defined herein. The
alkyl-derivatized amidino radicals are also referred to as
"alkylamidino" and "dialkylamidino," respectively.
[0036] "Cyano" refers to the --CN radical.
[0037] "Carboxy" refers to the --COOR radical, wherein R is
hydrogen or alkyl, as defined herein.
[0038] "Acyl" refers to the --COR radical, wherein R is alkyl,
aryl, cycloalkyl, heterocyclyl, as defined herein. For example, R
can be methyl, butenyl, cyclopropyl, and the like. The alkyl or
aryl can be optionally substituted with the substituents as
described for an alkyl or an aryl group, respectively. Exemplary
acyl groups include, without limitation, phenylacyl, benzylacyl,
C.sub.1-6acyl (e.g., acetyl) and the like.
[0039] "Alkylsulfonate" refers to --S(O).sub.2--OR radical, wherein
R is alkyl, as defined herein.
[0040] "Amidosulfonate" refers to the radical
--OS(O).sub.2--NR.sub.2, each R is independently hydrogen or alkyl.
Exemplary amidosulfonates include --OS(O).sub.2NH.sub.2,
--OS(O).sub.2NHMe.
[0041] "Aminocarbonyl" refers to the radical --C(O)NR.sub.2, each R
is independently hydrogen, alkyl, amino, cycloalkylalkyl,
heterocyclyl, alkoxyalkyl, hydroxyalkyl, hydroxyl, alkoxy,
arylalkyl, heterocyclylalkyl, or two R is together with the
nitrogen atom to which they are attached form a heterocyclyl, as
defined herein. When one of the R is hydrogen, the other R is
C1-4alkyl, aminocarbonyl can be represented by
"C.sub.1-4alkylformamidyl."
[0042] "N-formamidyl" refers to the radical --NHC(O)H.
[0043] "Phenylsulfonyl" refers to the --S(O).sub.2--R radical,
wherein R is phenyl, the phenyl can be further substituted with
alkyl or chloro.
[0044] "Phenylsulfonate" refers to the --O--S(O).sub.2--R radical,
wherein R is phenyl, the phenyl can be further substituted with
alkyl or chloro.
[0045] "Alkylsulfonyl" refers to the --S(O).sub.2--R radical,
wherein R is alkyl, as defined herein. Exemplary alkylsulfonyl
radicals include methylsulfonyl.
[0046] "Alkylthio" refers to the --SR radical wherein R is alkyl,
as defined herein.
[0047] "Arylthio" refers to the --SR radical wherein R is aryl, as
defined herein. The aryl group of the arylthio can be further
substituted with alkyl or chloro.
[0048] "Aryloxy" refers to the --OR radical wherein R is aryl, as
defined herein. The aryl group can be further substituted with
alkyl, alkoxy and the like.
[0049] "Acyloxyalkyl" refers to the --R'--OC(O)--R radical, wherein
R is alkyl, aryl, cycloalkyl, heterocyclyl, as defined herein; and
R' is an alkyl.
[0050] "Guanidino" refers to the --NH--C(.dbd.NH)--NH.sub.2
radical. One or both hydrogens of the amine group of the guanidino
may be replaced with one or two alkyl groups, as defined herein.
The alkyl-derivatized guanidine radicals are also referred to as
"alkylguanidino" and "dialkylguanidino," respectively.
[0051] "Nitro" refers to the --NO.sub.2 radical.
[0052] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms. An alkyl
may be saturated (containing carbons linked together by single
bonds only) or unsaturated (containing carbons linked together by
at least one double bond or triple bond.) An alkyl having one to
twelve carbon atoms is also referred to as "lower chain alkyl
moieties" and can be presented by "C.sub.1-12alkyl." In other
embodiments, an alkyl may comprise one to four carbon atoms and be
represented by "C.sub.1-4alkyl." In other embodiments, an alkyl may
comprise two to five carbon atoms and be represented by
"C.sub.2-5alkyl." An alkyl is attached to the rest of the molecule
by a single bond. Examples of saturated alkyls include, without
limitation, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),
n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,
2-methylhexyl, and the like. Examples of unsaturated alkyls
include, without limitation, ethenyl (i.e., vinyl), prop-1-enyl
(i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl
(i.e., acytylenyl), prop-1-ynyl and the like.
[0053] An alkyl may also be a monocyclic or bicyclic hydrocarbon
ring radical, which may include fused or bridged ring systems. A
cyclic alkyl is also referred to as "cycloalkyl." In certain
embodiments, a cycloalkyl may comprise three to six carbon atoms
and be represented by "C.sub.3-6cycloalkyl." Examples of monocyclic
cycloalkyl radicals include, e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An
unsaturated cycloalkyl contains an endo double bond (i.e., a double
bond in the ring). Examples of an unsaturated cycloalkyl include
cyclohexenyl. Examples of bicyclic cycloalkyl radicals include, for
example, norbornyl (i.e., bicyclo[2.2.1]heptyl),
7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.
[0054] Unless stated otherwise specifically in the specification,
the term "alkyl" is meant to include both alkyl and "substituted
alkyl," which refers to an alkyl radical in which one or more
hydrogen atoms are replaced by one or more substituents
independently selected from: acyl, amidino, alkylamidino,
dialkylamidino, alkoxy, aryl, cyano, cycloalkyl, guanidino,
alkylguanidino, dialkylguanidino, halo, heterocyclyl, hydrazinyl,
hydroxyl, nitro, --OC(O)--R.sup.11, --C(O)OR.sup.11,
--C(O)N(R.sup.11).sub.2, --N(R.sup.11)C(O)OR.sup.11,
--N(R.sup.11)C(O)R.sup.11, --N(R.sup.11)S(O).sub.tR.sup.11 (where t
is 1 or 2), --S(O).sub.tOR.sup.11 (where t is 1 or 2),
--S(O).sub.pR.sup.11 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.11).sub.2 (where t is 1 or 2) where each
R.sup.11 is independently hydrogen, alkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as defined herein.
[0055] "Alkoxy" refers to a radical represented by the formula
alkyl-O--, wherein alkyl is as defined herein. The alkyl portion
can be further substituted by one or more halogen. An alkoxy may
also be represented by the number of the carbons in the alkyl
group, for example, C.sub.1-6alkoxy or C.sub.1-3alkoxy.
[0056] "Aryl" refers to a radical derived from an aromatic
monocyclic or bicyclic ring system by removing a hydrogen atom from
a ring carbon atom. The aromatic monocyclic or bicyclic hydrocarbon
ring system comprises six to twelve carbon atoms (i.e.,
C.sub.6-12aryl), wherein at least one of the rings in the ring
system is fully unsaturated, i.e., it contains a cyclic,
delocalized (4n+2) .pi.--electron system in accordance with the
Huckel theory. Optionally, one or two ring atoms of the aryl may be
heteroatoms selected from nitrogen, oxygen or sulfur. Examples of
aryl radicals include, but are not limited to, phenyl and naphthyl.
Unless stated otherwise specifically in the specification, the term
"aryl" is meant to include both aryl and "substituted aryl," which
refers to an aryl radical in which one or more hydrogen atoms are
replaced by one or more substituents independently selected from:
alkyl, acyl, amidino, amidosulfonate, alkoxy, aryloxy, cyano,
guanidino, alkylguanidino, dialkylguanidino, halo, hydrazinyl,
hydroxyl, nitro, heterocyclyl, --OC(O)--R.sup.11,
--N(R.sup.11).sub.2, --C(O)OR.sup.11, --C(O)N(R.sup.11).sub.2,
--N(R.sup.11)C(O)OR.sup.11, --N(R.sup.11)C(O)R.sup.11,
--N(R.sup.11)S(O).sub.tR.sup.11 (where t is 1 or 2),
--S(O).sub.tOR.sup.11 (where t is 1 or 2), --S(O).sub.pR.sup.11
(where p is 0, 1 or 2), and --S(O).sub.tN(R.sup.11).sub.2 (where t
is 1 or 2) where each R.sup.11 is independently hydrogen, alkyl,
aryl, arylalkyl, heterocyclyl or heterocyclylalkyl.
[0057] "Arylalkyl" refers to an alkyl radical wherein one or more
hydrogens of the alkyl are replaced with one or more aryl groups,
as defined herein. In various embodiments, arylalkyls include from
7 to 15 carbons and can be represented by C.sub.7-15arylalkyl. In
certain embodiments, arylalkyl is arylC.sub.1-4alkyl wherein a
C.sub.1-4alkyl is substituted with one aryl or two aryl groups, the
latter being also referred to as "diarylalkyl" or "bisarylalkyl".
Examples of arylC.sub.1-4alkyl include, but are not limited to
arylmethyl, arylethyl, arylpropyl, arylbutyl, bisarylmethyl,
bisarylethyl, bisarylpropyl, bisarylbutyl. Exemplary arylalkyl
radicals include, without limitation, benzyl, naphthylmethyl,
diphenylmethyl, 3,3-bisphenylpropyl and the like. Unless stated
otherwise specifically in the specification, the term "arylalkyl"
is meant to include both arylalkyl and "substituted arylalkyl,"
wherein the alkyl part and/or the aryl part of the arylalkyl
radical may be substituted as described herein for the alkyl
radical and aryl radical, respectively.
[0058] "Cycloalkylalkyl" refers to an alkyl radical wherein one or
more hydrogens of the alkyl are replaced with one or more c groups,
as defined herein. In certain embodiments, cycloalkylalkyl is
cycloalkylC.sub.1-2alkyl such as cycloalkylmethyl, cycloalkylethyl
and the like. Exemplary cycloalkylalkyl radicals include, without
limitation, cyclohexylalkyl (e.g., cyclohexylmethyl and
cyclohexylethyl), and cyclopentylalkyl (e.g., cyclopentylmethyl and
cyclopentylethyl) and the like. Unless stated otherwise
specifically in the specification, the term "cycloalkylalkyl" is
meant to include both cycloalkylalkyl and "substituted
cycloalkylalkyl," wherein the alkyl part and/or the cycloalkyl part
of the cycloalkylalkyl radical may be substituted as described
herein for the alkyl radical and cycloalkyl radical,
respectively.
[0059] "Glycosyl" refers to a radical by removing the hemiacetal
hydroxyl group from a cyclic form of a monosaccharide (e.g.,
glucose), disaccharide, oligosaccharide (compring three to ten
monosaccharides), or polysaccharide (comprising more than ten
monosaccharides).
[0060] "Halo" or "halogen" refers to fluoro, chloro, bromo or iodo
radicals.
[0061] "Haloalkyl" refers to an alkyl radical, as defined herein,
which is substituted by one or more halo radicals, as defined
herein. Exemplary haloalkyls include, without limitation:
trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
An alkyl substituted with one or more fluoro is also referred to as
"perfluoroalkyl," for example, "perfluoC.sub.1-4alkyl." The alkyl
part of the haloalkyl radical may be optionally substituted as
defined herein for an alkyl group.
[0062] "Heterocyclyl" refers to a stable heterocyclic ring radical
that comprises two to eleven carbon atoms and from one to three
heteroatoms selected from nitrogen, oxygen and sulfur. In certain
embodiments, the heterocyclyl contains one or two heteroatoms.
Unless stated otherwise specifically in the specification, the
heterocyclyl radical may be a monocyclic or bicyclic ring system,
which may include fused or bridged ring systems. In certain
embodiments, the heterocyclyl may be a 5-, 6- or 7-membered
monocyclic ring. In other embodiments, the heterocyclyl may be an
8-, 9-, 10-, 11- or 12-membered fused bicyclic ring. The
heteroatoms in the heterocyclyl radical may be optionally oxidized.
One or more nitrogen atoms, if present, may be optionally
quaternized. The heterocyclyl radical may be non-aromatic or
aromatic (i.e., at least one ring in the heterocyclyl radical has a
delocalized (4n+2) .pi.-electron system in accordance with the
Huckel theory.) The heterocyclyl may be attached to the rest of the
molecule through any atom of the ring(s). Examples of non-aromatic
heterocyclyl radicals include, but are not limited to, dioxolanyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl (also referred to as
"piperidyl"), piperazinyl, 4-piperidonyl, 3-pyrrolinyl,
pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
and thiamorpholinyl. Examples of aromatic heterocyclyl radicals
include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,
benzooxazolyl, benzoisoxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,
benzopyranyl, benzopyrazolyl, benzofuranyl, benzofuranonyl,
benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl,
benzotriazolyl, carbazolyl, chromone, cinnolinyl,
cyclopenta[d]pyrimidinyl, dibenzofuranyl, dibenzothiophenyl,
furanyl, furanonyl, furo[3,2-c]pyridinyl, isothiazolyl, imidazolyl,
indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,
isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,
purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl
(also referred to as pyridyl), pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 1,2,3,4-tetrahydrocarbazolyl,
5,6,7,8-tetrahydroquinazolinyl, thiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, triazin-2-yl, thieno[2,3-d]pyrimidinyl,
thieno[3,2-c]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl
(i.e. thienyl). Unless stated otherwise specifically in the
specification, the twin "heterocyclyl" is meant to include both
heterocyclyl and "substituted heterocyclyl," which refers to a
heterocyclyl radical substituted by one or more substituents
selected from alkyl, acyl, oxo (e.g., pyridinonyl, pyrrolidonyl),
aryl, arylalkyl, acyloxyalkyl, amidino, alkoxy, cyano, guanidino,
alkylpanidino, dialkylguanidino, halo, hydrazinyl, hydroxyl, nitro,
--OC(O)--R.sup.11, --N(R.sup.11).sub.2, --C(O)OR.sup.11,
--C(O)N(R.sup.11).sub.2, --N(R.sup.11)C(O)OR.sup.11,
--N(R.sup.11)C(O)R.sup.11, --N(R.sup.11)S(O).sub.tR.sup.11 (where t
is 1 or 2), --S(O).sub.tOR.sup.11 (where t is 1 or 2),
--S(O).sub.pR.sup.11 (where p is 0, 1 or 2), and
--S(O).sub.tN(R.sup.11).sub.2 (where t is 1 or 2) where each
R.sup.11 is independently hydrogen, alkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl.
[0063] "Heterocyclylalkyl" refers to an alkyl radical wherein one
or more hydrogens of the alkyl are replaced with one or more
heterocyclyl groups, as defined herein. If the heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl may be attached
to the alkyl radical at the nitrogen atom. In certain embodiments,
the alkyl part of the heterocyclylalkyl contains 1-4 carbon atoms
and can be represented by heterocyclylC.sub.1-4alkyl. Examples of
heterocyclylalkyl radicals include, without limitation,
morpholinylalkyl such as morpholinylmethyl, piperidylalkyl such as
piperidylmethyl, imidazolidinylalkyl such as imidazolidinylmethyl
and the like. Additional examples of heterocyclylalkyl radicals,
wherein the heterocyclyl part is aromatic, include, but are not
limited to: pyridylmethyl, pyridylethyl, pyridylpropyl,
pyridylbutyl, quinolinylmethyl, quinolinylethyl, quinolinylpropyl,
quinolinylbutyl, indazolylmethyl, indazolylethyl, indazolylpropyl,
indazolylbutyl, benzpyrazolylmethyl, benzpyrazolylethyl,
benzpyrazolylpropyl, benzpyrazolylbutyl, isoquinolinylmethyl,
isoquinolinylethyl, isoquinolinylpropyl, iso quinolinylbutyl,
benzotriazolylmethyl, benzotriazolylethyl, benzotriazolylpropyl,
benzotriazolylbutyl and the like. Unless stated otherwise
specifically in the specification, the term "heterocyclylalkyl" is
meant to include both heterocyclylalkyl and "substituted
heterocyclylalkyl," wherein the alkyl part and/or the heterocyclyl
part of the heterocyclylalkyl radical may be substituted as
described herein for the alkyl radical and the heterocyclyl
radical, respectively.
[0064] The compounds, or their pharmaceutically acceptable salts
may contain one or more asymmetric centers and may thus give rise
to enantiomers, diastereomers, and other stereoisomeric forms that
may be defined, in terms of absolute stereochemistry, as (R)- or
(S)- or, as (D)- or (L)-for amino acids. When the compounds
described herein contain olefinic double bonds or other centers of
geometric asymmetry, and unless specified otherwise, it is intended
that the compounds include both E and Z geometric isomers (e.g., ds
or trans.) Likewise, all possible isomers, as well as their racemic
and optically pure forms, and all tautomeric forms are also
intended to be included.
[0065] As used herein, "amino acid" is meant to include naturally
occurring .alpha.-amino acids and/or unnatural amino acids, such as
.beta.-amino acids and homoamino acids. Examples of the amino acids
include, but are not limited to: alanine, arginine, asparagine,
aspartic acid, cysteine, glutamine, glutamic acid, glycine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
proline, serine, threonine, tryptophan, tyrosine, valine,
phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline,
hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate,
hippuric acid, octahydroindole-2-carboxylic acid, statine,
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,
ornithine, 3-methylhistidine, norvaline, beta-alanine,
gamma-aminobutylic acid, cirtulline, homocysteine, homoserine,
methyl-alanine, para-benzoylphenylalanine, phenylglycine,
propargylglycine, sarcosine, methionine sulfone, tort-butylglycine,
3,5-dibromotyrosine and 3,5-diiodotyrosine.
[0066] "Amino acid residue" or "amino acid side chain moiety"
refers to the portion of an amino acid that remains after losing a
water molecule (or alcohol) when the amino acid is condensed with a
molecule. Typically, an amino acid is condensed with a molecule,
including a compound of any of Formulae (I)-(IV), by forming a
peptide bond. In certain embodiments, the amino functional group of
the amino acid can be condensed with a carboxylic acid group or its
reactive equivalent (e.g., carboxylic anhydride) of the molecule.
In other embodiments, the carboxylic acid functional group of the
amino acid can be condensed with an amine group of the molecule.
Typically, a molecule of water is lost during the formation of the
peptide bond. Examples of the "amino acid residues" or "amino acid
side chain moiety" include, but are not limited to, residues of
alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,
glutamic acid, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine,
4-hydroxyproline, hydroxylysine, demosine, isodemosine,
gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic
acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, ornithine, 3-methylhistidine, norvaline,
beta-alanine, gamma-aminobutylic acid, cirtulline, homocysteine,
homoserine, methyl-alanine, para-benzoylphenylalanine,
phenylglycine, propargylglycine, sarcosine, methionine sulfone,
tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine,
glycosylated threonine, glyclosylated serine, and glycosylated
asparagine.
[0067] An "amino acid side chain derivative" refers to a derivative
of any of the amino acid side chain moiety as described in Table 1.
In certain embodiments, the amino acid side chain derivative is
alkyl, acyl, alkoxy, aryl, arylalkyl, heterocyclyl, or
heterocyclylalkyl, as defined herein.
TABLE-US-00001 TABLE 1 Amino Acid Side Chain Moiety Amino Acid --H
Glycine --CH.sub.3 Alanine --CH(CH.sub.3).sub.2 Valine
--CH.sub.2CH(CH.sub.3).sub.2 Leucine --CH(CH.sub.3)CH.sub.2CH.sub.3
Isoleucine --(CH.sub.2).sub.4NH.sub.3.sup.+ Lysine
--(CH.sub.2).sub.3NHC(NH.sub.2)NH.sub.2.sup.+ Arginine ##STR00005##
Histidine --CH.sub.2COO.sup.- Aspartic acid
--CH.sub.2CH.sub.2COO.sup.- Glutamic acid --CH.sub.2CONH.sub.2
Asparagine --CH.sub.2CH.sub.2CONH.sub.2 Glutamine ##STR00006##
Phenylalanine ##STR00007## Tyrosine ##STR00008## Tryptophan
--CH.sub.2SH Cysteine --CH.sub.2CH.sub.2SCH.sub.3 Methionine
--CH.sub.2OH Serine --CH(OH)CH.sub.3 Threonine ##STR00009## Proline
##STR00010## Hydroxyproline
[0068] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. It is
therefore contemplated that various stereoisomers and mixtures
thereof and includes "enantiomers," which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0069] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule.
[0070] "Prodrugs" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound described herein. Thus, the term
"prodrug" refers to a precursor of a biologically active compound
that is pharmaceutically acceptable. A prodrug may be inactive when
administered to a subject, but is converted in vivo to an active
compound, for example, by hydrolysis. The prodrug compound often
offers advantages of solubility, tissue compatibility or delayed
release in a mammalian organism (see, Bundgard, H., Design of
Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
[0071] A discussion of prodrugs is provided in Higuchi, T., et al.,
"Pro-drugs as Novel Delivery Systems," A. C. S. Symposium Series,
Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated in full by reference
herein.
[0072] The term "prodrug" is also meant to include any covalently
bonded carriers, which release the active compound in vivo when
such prodrug is administered to a mammalian subject. Prodrugs of an
active compound, as described herein, may be prepared by modifying
functional groups present in the active compound in such a way that
the modifications are cleaved, either in routine manipulation or in
vivo, to the parent active compound. Prodrugs include compounds
wherein a hydroxyl, amino or mercapto group is bonded to any group
that, when the prodrug of the active compound is administered to a
mammalian subject, cleaves to form a free hydroxyl, free amino or
free mercapto group, respectively. Examples of the prodrugs
include, but are not limited to, acetate, succinate, phosphate,
hemisuccinate, malate, hemimalate, formate and benzoate derivatives
of alcohol or amine functional groups in the active compounds and
the like. Other examples of the prodrugs include, but are not
limited to, amino acid derivatives of alcohol or amine functional
groups in the active compounds and the like.
[0073] The present invention is directed to conformationally
constrained compounds that mimic the secondary structure of
reverse-turn regions of biological peptide and proteins (also
referred to herein as "reverse-turn mimetics," and is also directed
to chemical libraries relating thereto.
[0074] The reverse-turn mimetic structures of the present invention
are useful as bioactive agents, including (but not limited to) use
as diagnostic, prophylactic and/or therapeutic agents. The
reverse-turn mimetic structure libraries of this invention are
useful in the identification of bioactive agents having such uses.
In the practice of the present invention, the libraries may contain
from tens to hundreds to thousands (or greater) of individual
reverse-turn structures (also referred to herein as "members").
[0075] In one aspect of the present invention, a reverse-turn
mimetic structure is disclosed having the following Formula
(I):
##STR00011##
wherein E is --ZR.sub.3-- or --(C.dbd.O)--, wherein Z is CH or N; W
is --(C.dbd.O)--, --(C.dbd.O)NH--, --(C.dbd.O)O--, --(C.dbd.O)S--,
--S(O).sub.2-- or a bond; and each of R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is the same or different and independently an
amino acid side chain moiety or an amino acid side chain
derivative. The reverse turn mimetic compound may be present as an
isolated stereoisomer or a mixture of stereoisomers or as a
pharmaceutically acceptable salt thereof.
[0076] In certain embodiments, R.sub.1 of compounds of Formula (I)
is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl,
pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl,
benzothiazolyl, substituted benzothiazolyl, benzimidazolyl,
substituted benzimidazolyl, benzothiophenyl, substituted
benzothiophenyl, benzodioxolyl, substituted benzodioxolyl,
benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted
benzisoxazolyl, chromonyl, substituted chromonyl,
tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or
substituted benzyl, aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl.
[0077] In certain embodiments, R.sub.1 of compounds of Formula (I)
may be:
[0078] substituted phenyl having one or more substituents
independently selected from: halogen, nitro, cyano, hydroxyl,
C.sub.1-12alkoxy, substituted C.sub.1-12alkoxy, C.sub.1-12alkyl,
carbonyl, carboxy, acetyl, C.sub.1-12alkylthio, C.sub.6-12arylthio,
thiophenyl, sulfonyl, C.sub.6-12aryloxy, substituted
C.sub.6-12aryloxy, indanyloxy, amino,
aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone,
phosphatemethyl, and imidazolyl;
[0079] substituted pyridinyl having one or more substituents
independently selected from: halogen, cycloalkyl, phenyl,
substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl,
C.sub.1-12alkyl, carbonyl, amide, and carboxy;
[0080] substituted pyrimidinyl having one or more substituents
independently selected from phenyl and amino;
[0081] substituted indolyl having one or more substituents
independently selected from: phenyl, substituted phenyl,
substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl, carbonyl,
C.sub.1-12alkyl, acyloxy C.sub.1-12alkyl, C.sub.1-12alkoxy,
halogen, monoxide, and cyano;
[0082] substituted benzothiazolyl having one or more substituents
independently selected from: halogen, and phosphate disodium
amino;
[0083] substituted benzimidazolyl having one or more substituents
independently selected from: carbonyl, monoxide, thio,
perfluoroC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, and
C.sub.1-12alkyl;
[0084] substituted benzothiophenyl having one or more substituents
independently selected from: nitro, amino, C.sub.1-4alkylamino,
bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo,
aldoamino, and carbonyl;
[0085] substituted benzodioxolyl having one or more substituents
independently selected from: nitro and halogen;
[0086] substituted benzoxazolyl having one or more substituents
independently selected from: monoxide, and thio;
[0087] substituted benzisoxazolyl having one or more substituents
independently selected from: amino;
[0088] substituted chromonyl having one or more substituents
independently selected from: phenyl; or
[0089] substituted tetrahydro-carbazolyl having one or more
substituents independently selected from: sulfonyl.
[0090] In certain embodiment of the compounds described in the
preceding paragraph,
[0091] substituted phenyl is halo-phenyl, cyano phenyl,
C.sub.1-12alkoxy phenyl, hydroxy phenyl, carboxy phenyl, acetamide
phenyl, aminocarbonyl phenyl, amino phenyl, alkylsulfonyl phenyl,
or alkylthio phenyl;
[0092] substituted benzyl is nitro-benzyl, or amino-benzyl;
[0093] amide group is C.sub.1-6alkylamide, carbamide,
C.sub.1-6alkycarbamide, C.sub.1-6alkylcarbamate,
C.sub.1-6alkylalkoxycarbamate, formamide, C.sub.1-6alkylformamide,
carbamoylurea, or acetamide;
[0094] carbonyl group is cycloalkylcarbonyl,
C.sub.1-12alkoxycarbonyl, morpholinylcarbonyl, aminocarbonyl,
C.sub.1-12alkylaminocarbonyl, di C.sub.1-12alkylaminocarbonyl,
C.sub.1-12alkynylaminocarbonyl, C.sub.2-13alkoxyalkylaminocarbonyl
thiophenyl C.sub.1-12alkylaminocarbonyl, benzylaminocarbonyl,
dihydropyrrolylcarbonyl, cycloalkyl C.sub.1-12alkylcarbonyl,
cycloalkenyl C.sub.1-12alkylcarbonyl,
C.sub.2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl,
piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl,
hydroxyaminocarbonyl, hydroC.sub.1-12alkylaminocarbonyl,
hydrazinylcarbonyl, C.sub.1-12alkylformatehydrazinylcarbonyl, or
tetrahydrofuranylC.sub.1-12alkylaminocarbonyl;
[0095] sulfonyl group is tosyl, phenyl sulfonyl, C.sub.1-12alkyl
sulfonyl, C.sub.1-12alkylsulfonylamino, aminosulfonylamino or
halo-phenyl sulfonyl;
[0096] substituted alkoxy is morpholinyl C.sub.1-12alkoxy,
dihalo-C.sub.1-12alkoxy, or piperazinyl C.sub.1-12alkoxy;
[0097] substituted aryloxy is halo-C.sub.6-12aryloxy;
[0098] substituted pyridinyl is halo-pyridinyl, C.sub.1-12alkoxy
pyridinyl, amino pyridinyl, or morpholinyl pyridinyl; or
[0099] substituted tetrahydro-carbazolyl is
phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
[0100] In certain embodiments, R.sub.2, R.sub.4 and R.sub.5 of
compounds of Formula (I) are independently selected from the group
consisting of
[0101] C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or
more substituents independently selected from: halogen, cyano,
C.sub.1-6alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, aminocarbonyl, morpholinyl,
methyl-piperazinyl, phenyl and hydroxyl;
[0102] C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl having
one or more substituents independently selected from: amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0103] C.sub.6-12aryl or substituted C.sub.6-12aryl having one or
more substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0104] C.sub.1-6alkoxy, diC.sub.1-5alkylamino;
C.sub.6-13heterocyclylalkyl, which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur, or substituted
C.sub.6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur and has one or more substituents
independently selected from: halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, cyano, amino, amide, monoxide, thio, and hydroxyl;
and
[0105] C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl
having one or more substituents independently selected from: amino,
amidino, amide, hydroxyC.sub.1-4alkyl, dihydroxyC.sub.1-4alkyl,
urea, thiourea, ureaC.sub.1-4alkyl, carbamoylurea, carbonyl,
carbonylamino, aminosulfo, amidesulfo, acetylenyl, allyl,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; and
[0106] R.sub.3 is selected from the group consisting of:
[0107] hydrogen;
[0108] C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or
more substituents independently selected from: halogen, cyano,
C.sub.1-6alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0109] C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl having
one or more substituents independently selected from: amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0110] C.sub.6-12aryl or substituted C.sub.6-12aryl having one or
more substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, and hydroxyl;
[0111] C.sub.1-6alkoxy;
[0112] C.sub.6-13heterocyclylalkyl, which has 1 to 2 heteroatoms
selected from nitrogen, oxygen or sulfur, or substituted
C.sub.6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur and has one or more substituents
independently selected from: halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, cyano, and hydroxyl; and
[0113] C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-6alkyl,
C.sub.1-6alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl.
[0114] In certain embodiments, R.sub.2, R.sub.4 and R.sub.5 of
compounds of Formula (I) are independently selected from the group
consisting of:
[0115] aminoC.sub.2-5alkyl; guanidinoC.sub.2-5alkyl;
C.sub.1-4alkylguanidinoC.sub.2-5alkyl,
diC.sub.1-4alkylguanidino-C.sub.2-5alkyl; amidinoC.sub.2-5alkyl;
C.sub.1-4alkylamidinoC.sub.2-5alkyl;
diC.sub.1-4alkylamidinoC.sub.2-5alkyl; C.sub.1-3alkoxy;
[0116] C.sub.1-12alkyl; C.sub.6-12aryl; C.sub.6-12arylalkyl;
C.sub.2-12alkenyl;
[0117] phenyl or substituted phenyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen,
perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro,
carboxy, cyano, sulfuryl and hydroxyl;
[0118] naphthyl or substituted naphthyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl, and hydroxyl;
[0119] benzyl or substituted benzyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano,
C.sub.1-4alkyl, carbonyl, aminoC.sub.1-4alkyl, acetylenyl, sulfuryl
and hydroxyl;
[0120] bisphenylmethyl or substituted bisphenylmethyl having one or
more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1.
[0121] 4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl;
pyridinyl or substituted pyridinyl having one or more substituents
independently selected from: amino, amide, monoxide, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0122] pyridinylC.sub.1-4alkyl, or substituted
pyridinylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amide, monoxide, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0123] pyrimidinylC.sub.1-4alkyl, or substituted
pyrimidinylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl, monoxide, amide, and hydroxyl;
[0124] triazin-2-ylC.sub.1-4alkyl, or substituted
triazin-2-ylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0125] imidazolylC.sub.1-4alkyl or substituted
imidazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl, monoxide and hydroxyl;
[0126] tetrazolylC.sub.1-4alkyl or substituted
tetrazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0127] triazolylC.sub.1-4alkyl or substituted
triazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0128] indolylC.sub.1-4alkyl or substituted indolylC.sub.1-4alkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-4alkyl,
C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0129] indazolylC.sub.1-4alkyl or substituted
indazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0130] benzoxazolylC.sub.1-4alkyl or substituted
benzoxazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0131] benzimidazolylC.sub.1-4alkyl or substituted
benzimidazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, thio, monoxide and hydroxyl;
[0132] benzotriazolylC.sub.1-4alkyl or substituted
benzotriazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0133] benzodioxolylC.sub.1-4alkyl, substituted
benzodioxolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, monoxide and hydroxyl;
[0134] N-amidinopiperazinyl-N--C.sub.0-4alkyl,
N-amidinopiperidinylC.sub.1-4alkyl;
[0135] 4-aminocyclohexylC.sub.0-2alkyl; thiophenylC.sub.1-4alkyl,
bipiperidinylcarbonyloxy; amideC.sub.1-4alkyl; ureaC.sub.1-4alkyl;
amino C.sub.1-4alkyl; cycloalkylC.sub.1-4alkyl and
diaminosulfurylC.sub.1-4alkyl; and
[0136] R.sub.3 is selected from the group consisting of:
[0137] hydrogen; aminoC.sub.2-5alkyl; guanidinoC.sub.2-5alkyl;
C.sub.1-4alkylguanidinoC.sub.2-5alkyl,
diC.sub.1-4alkylguanidino-C.sub.2-5alkyl; amidinoC.sub.2-5alkyl;
C.sub.1-4alkylamidinoC.sub.2-5alkyl;
diC.sub.1-4alkylamidinoC.sub.2-5alkyl; C.sub.1-3alkoxy;
[0138] C.sub.1-12alkyl; C.sub.6-12aryl; C.sub.6-12arylalkyl;
C.sub.2-12alkenyl;
[0139] phenyl or substituted phenyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen,
perfluoroC.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano,
sulfuryl and hydroxyl;
[0140] naphthyl or substituted naphthyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl, and hydroxyl;
[0141] benzyl or substituted benzyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl
and hydroxyl;
[0142] bisphenylmethyl or substituted bisphenylmethyl having one or
more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl
and hydroxyl;
[0143] pyridinyl or substituted pyridinyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0144] pyridinylC.sub.1-4alkyl, or substituted
pyridinylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0145] pyrimidinylC.sub.1-4alkyl, or substituted
pyrimidinylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl
and hydroxyl;
[0146] triazin-2-ylC.sub.1-4alkyl, or substituted
triazin-2-ylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0147] imidazolylC.sub.1-4alkyl or substituted
imidazolylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0148] N-amidinopiperazinyl-N--C.sub.0-4alkyl,
N-amidinopiperidinylC.sub.1-4alkyl; and
[0149] 4-aminocyclohexylC.sub.0-2alkyl.
[0150] In certain embodiments, R.sub.2, R.sub.4 and R.sub.5 of
compounds of Formula (I) are independently selected from the group
consisting of:
[0151] C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or
more substituents independently selected from acyl, carboxy,
alkylthio, aminocarbonyl, morpholinyl, methyl-piperazinyl, phenyl,
cyano, C.sub.1-5alkylamino, diC.sub.1-5alkylamino, hydroxyl,
C.sub.1-6alkoxy, and phenylsulfonyl;
[0152] C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl having
one or more substituents independently selected from acyl, carboxy,
alkylthio, and phenylsulfonyl;
[0153] substituted C.sub.6-12aryl substituted with
amidosulfonate;
[0154] arylC.sub.1-4alkyl or substituted arylC.sub.1-4alkyl having
one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4dialkylamino,
C.sub.3-6cycloalkyl, halogen, perfluoroC.sub.1-4alkyl,
C.sub.1-6alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl,
hydroxyl, C.sub.1-6alkyloxyC.sub.1-6acyl,
morphorlinylC.sub.1-6alkyl, aryl, aryloxy, (alkyl)(arylalkyl)amino,
heterocyclyl, acyl, amidosulfonate, aminocarbonyl, alkylsulfonate,
alkylsulfonyl, alkylthio, arylthio, phenylsulfonate,
phenylsulfonyl, morphorlinylC.sub.1-3alkoxy, N-formamidyl, amide,
hydroxyC.sub.1-4alkyl, dihydroxyC.sub.1-4alkyl, urea, thiourea,
ureaC.sub.1-4alkyl, carbamoylurea, carbonyl, carbonylamino,
aminosulfo, amidesulfo, aminoC.sub.1-4alkyl, allyl, acetylenyl, and
pyrrolidonyl;
[0155] heterocyclyl or substituted heterocyclyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-6alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl;
[0156] heterocyclylC.sub.1-4alkyl or substituted
heterocyclylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amide, monoxide, thio, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
C.sub.3-6cycloalkyl, halogen, perfluoroC.sub.1-4alkyl,
C.sub.1-6alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl,
hydroxyl, C.sub.1-6alkyloxyC.sub.1-6acyl,
morphorlinylC.sub.1-6alkyl, arylalkyl, aryl, heterocyclyl, acyl,
phenylsulfonyl, cycloalkylalkyl, acyloxyalkyl, aminocarbonyl, and
C.sub.1-6alkylformamidyl;
[0157] cycloalkyl or substituted cycloalkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4dialkylamino, halogen, perfluoro
C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl; and
[0158] cycloalkylalkyl or substituted cycloalkylalkyl having one or
more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl; and
[0159] R.sub.3 is selected from the group consisting of:
[0160] hydrogen;
[0161] C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or
more substituents independently selected from acyl, carboxy,
alkylthio, and phenylsulfonyl;
[0162] C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl having
one or more substituents independently selected from acyl, carboxy,
alkylthio, and phenylsulfonyl;
[0163] substituted C.sub.6-12aryl substituted with
amidosulfonate;
[0164] arylC.sub.1-4alkyl or substituted arylC.sub.1-4alkyl having
one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4dialkylamino,
C.sub.3-6cycloalkyl, halogen, perfluoroC.sub.1-4alkyl,
C.sub.1-6alkyl, C.sub.1-3alkoxy, nitro, carboxy, cyano, sulfuryl,
hydroxyl, C.sub.1-6alkyloxyC.sub.1-6acyl,
morphorlinylC.sub.1-6alkyl, aryl, aryloxy, (alkyl)(arylalkyl)amino,
heterocyclyl, acyl, amidosulfonate, aminocarbonyl, alkylsulfonate,
alkylsulfonyl, alkylthio, arylthio, phenylsulfonate,
phenylsulfonyl, morphorlinylC.sub.1-3alkoxy, N-formamidyl, and
pyrrolidonyl;
[0165] heterocyclyl or substituted heterocyclyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-3alkoxy, nitro, carboxy,
cyano, sulfuryl and hydroxyl;
[0166] heterocyclylC.sub.1-4alkyl or substituted
heterocyclylC.sub.1-4alkyl having one or more substituents
independently selected from: amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, C.sub.3-6cycloalkyl,
halogen, perfluoroC.sub.1-4alkyl, C.sub.1-6alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl, hydroxyl,
C.sub.1-6alkyloxyC.sub.1-6acyl, morphorlinylC.sub.1-6alkyl,
arylalkyl, aryl, heterocyclyl, acyl, phenylsulfonyl,
cycloalkylalkyl, acyloxyalkyl, aminocarbonyl and
C.sub.1-4alkylformamidyl;
[0167] cycloalkyl or substituted cycloalkyl having one or more
substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl; and
[0168] cycloalkylalkyl or substituted cycloalkylalkyl having one or
more substituents independently selected from: amino, amidino,
guanidino, hydrazino, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
halogen, perfluoro C.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3alkoxy,
nitro, carboxy, cyano, sulfuryl and hydroxyl.
[0169] In certain embodiment of the compounds described in the
preceding paragraph, arylC.sub.1-4alkyl is benzyl, bisphenylmethyl,
naphthylmethyl or 3,3-bisphenylpropyl; and
[0170] heterocyclylC.sub.1-4alkyl is benzotriazolylC.sub.1-4alkyl,
benzopyrazolylC.sub.1-4alkyl, indazolylC.sub.1-4alkyl,
isoquinolylC.sub.1-4alkyl, benzothiazolylC.sub.1-4alkyl,
quinolinylC.sub.1-4alkyl, imidazolinylC.sub.1-4alkyl,
thienylC.sub.1-4alkyl, tetrahydrofuranylC.sub.1-4alkyl,
pyridinylC.sub.1-4alkyl, pyrimidinylC.sub.1-4alkyl,
benzimidazolylC.sub.1-4alkyl, thiophenylC.sub.1-4alkyl
tetrazolylC.sub.1-4alkyl, benzoxazolylC.sub.1-4alkyl,
benzodioxolylC.sub.1-4alkylor indolylC.sub.1-4alkyl.
[0171] In the embodiment where E is CHR.sub.3, the reverse turn
mimetic compound of this invention has a structure of Formula
(II):
##STR00012##
wherein W is --(C.dbd.O)--, --(C.dbd.O)NH--, --(C.dbd.O)O--,
--(C.dbd.O)S--, --S(O).sub.2-- or a bond; and each of R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is the same or different and
independently an amino side chain moiety or an amino acid side
chain derivative.
[0172] In certain embodiments, R.sub.1 of compounds of Formula (II)
is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl,
pyrimidinyl, substituted pyrimidinyl, indolyl, substituted indolyl,
benzothiazolyl, substituted benzothiazolyl, benzimidazolyl,
substituted benzimidazolyl, benzothiophenyl, substituted
benzothiophenyl, benzodioxolyl, substituted benzodioxolyl,
benzoxazolyl, substituted benzoxazolyl, benzisoxazolyl, substituted
benzisoxazolyl, chromonyl, substituted chromonyl,
tetrahydro-carbazolyl, substituted tetrahydro-carbazolyl, benzyl or
substituted benzyl, aminocarbonylC.sub.1-6alkyl,
C1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl, dibenzofuranyl,
acetylenyl, or styrenyl.
[0173] In certain embodiment of the compounds described in the
preceding paragraph,
[0174] R.sub.2, R.sub.4 and R.sub.5 are independently selected from
the group consisting of:
[0175] C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or
more substituents independently selected from: halogen, cyano,
C.sub.1-6alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, aminocarbonyl, morpholinyl,
methyl-piperazinyl, phenyl, and hydroxyl;
[0176] C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl having
one or more substituents independently selected from: amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0177] C.sub.6-12aryl or substituted C.sub.6-12aryl having one or
more substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, and hydroxyl;
[0178] C.sub.1-6alkoxy; diC.sub.1-5alkylamino;
[0179] C.sub.6-13heterocyclylalkyl, which has 1 to 2 heteroatoms
selected from nitrogen, oxygen or sulfur, or substituted
C.sub.6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur and has one or more substituents
independently selected from: halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, cyano, amino, amidino, guanidino, hydrazino,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
perfluoroC.sub.1-4alkyl, nitro, carboxy, carbonyl,
aminoC.sub.1-4alkyl, sulfuryl, thio, monoxide and hydroxyl; and
[0180] C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-6alkyl,
C.sub.1-6alkoxy, nitro, carboxy, cyano, sulfuryl, amide,
hydroxyC.sub.1-4alkyl, dihydroxyC.sub.1-4alkyl, urea, thiourea,
ureaC.sub.1-4alkyl, carbamoylurea, carbonyl, carbonylamino,
aminosulfo, amidesulfo, aminoC.sub.1-4alkyl, allyl, C.sub.1-4alkyl,
aminoC.sub.1-4alkyl, acetylenyl, hydroxyl, phosphate,
dimethylaminoacetate, dimethylaminoalkylcarbamate, and
diethyl-phosphono-acetamido; and
[0181] R.sub.3 is selected from the group consisting of
[0182] hydrogen;
[0183] C.sub.1-12alkyl or substituted C.sub.1-12alkyl having one or
more substituents independently selected from: halogen, cyano,
C.sub.1-6alkoxy, amino, guanidino, C.sub.1-4alkylguanidino,
diC.sub.1-4alkylguanidino, amidino, C.sub.1-4alkylamidino,
diC.sub.1-4alkylamidino, C.sub.1-5alkylamino,
diC.sub.1-5alkylamino, and hydroxyl;
[0184] C.sub.2-12alkenyl or substituted C.sub.2-12alkenyl having
one or more substituents independently selected from: amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0185] C.sub.6-12aryl or substituted C.sub.6-12aryl having one or
more substituents independently selected from: halogen, amino,
guanidino, C.sub.1-4alkylguanidino, diC.sub.1-4alkylguanidino,
amidino, C.sub.1-4alkylamidino, diC.sub.1-4alkylamidino,
C.sub.1-5alkylamino, diC.sub.1-5alkylamino, and hydroxyl;
[0186] C.sub.1-6alkoxy;
[0187] C.sub.6-13heterocyclylalkyl, which has 1 to 2 heteroatoms
selected from nitrogen, oxygen or sulfur, or substituted
C.sub.6-13heterocyclylalkyl which has 1 to 2 heteroatoms selected
from nitrogen, oxygen or sulfur and has one or more substituents
independently selected from: halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, cyano, and hydroxyl; and
[0188] C.sub.7-13arylalkyl or substituted C.sub.7-13arylalkyl
having one or more substituents independently selected from: amino,
amidino, guanidino, hydrazino, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, halogen, perfluoro C.sub.1-6alkyl,
C.sub.1-6alkoxy, nitro, carboxy, cyano, sulfuryl and hydroxyl.
[0189] In certain embodiment of the compounds described in the
preceding paragraph, R.sub.1 of compounds of Formula (II) is
selected from the group consisting of substituted phenyl having one
or more substituents independently selected from: halogen, nitro,
cyano, hydroxyl, C.sub.1-12alkoxy, substituted C.sub.1-12alkoxy,
C.sub.1-12alkyl, carbonyl, carboxy, acetyl, C.sub.1-12alkylthio,
C.sub.6-12arylthio, thiophenyl, sulfonyl, C.sub.6-12aryloxy,
substituted C.sub.6-12aryloxy, indanyloxy, amino,
aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and
imidazolyl;
[0190] substituted pyridinyl having one or more substituents
independently selected from: halogen, cycloalkyl, phenyl,
substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl,
C.sub.1-12alkyl, carbonyl, amide, and carboxy;
[0191] substituted pyrimidinyl having one or more substituents
independently selected from phenyl and amino;
[0192] substituted indolyl having one or more substituents
independently selected from: phenyl, substituted phenyl,
substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl, carbonyl,
C.sub.1-12alkyl, acyloxy C.sub.1-12alkyl, C.sub.1-12alkoxy,
halogen, monoxide, and cyano;
[0193] substituted benzimidazolyl having one or more substituents
independently selected from: carbonyl, monoxide, thio,
perfluoroC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, and
C.sub.1-12alkyl;
[0194] substituted benzothiophenyl having one or more substituents
independently selected from: nitro, amino, C.sub.1-4alkylamino,
bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo,
aldoamino, and carbonyl;
[0195] substituted benzodioxolyl having one or more substituents
independently selected from: nitro and halogen;
[0196] substituted benzoxazolyl having one or more substituents
independently selected from: monoxide, and thio;
[0197] substituted benzisoxazolyl having one or more substituents
independently selected from: amino;
[0198] substituted chromonyl having one or more substituents
independently selected from: phenyl; and
[0199] substituted tetrahydro-carbazolyl having one or more
substituents independently selected from: sulfonyl;
[0200] R.sub.2 and R.sub.5 are independently C.sub.1-12alkyl,
C.sub.6-12aryl, C.sub.7-12arylalkyl, C.sub.6-11heterocyclylalkyl,
hydroxybenzyl, or substituted benzyl having a substituents selected
from phosphate, dimethylaminoacetate,
(2-dimethylamino-ethyl)-carbamate, and
diethyl-phosphono-acetamido;
[0201] R.sub.3 is hydrogen or C.sub.1-12alkyl; and
[0202] R.sub.4 is C.sub.1-12alkyl, C.sub.7-12arylalkyl, or
C.sub.2-12alkenyl.
[0203] In certain embodiment of the compounds described in the
preceding paragraph, substituted phenyl is halo-phenyl, cyano
phenyl, C.sub.1-12alkoxy phenyl, hydroxy phenyl, carboxy phenyl,
acetamide phenyl, aminocarbonyl phenyl, amino phenyl, alkylsulfonyl
phenyl, or alkylthio phenyl;
[0204] substituted benzyl is nitro-benzyl, or amino-benzyl;
[0205] amide group is C.sub.1-6alkylamide, carbamide,
C.sub.1-6alkylcarbamide, C.sub.1-6alkylcarbamate,
C.sub.1-6alkylalkoxycarbamate, formamide, C.sub.1-6alkylformamide,
carbamoylurea, or acetamide;
[0206] carbonyl group is cycloalkylcarbonyl,
C.sub.1-12alkoxycarbonyl, morpholinylcarbonyl, aminocarbonyl,
C.sub.1-12alkylaminocarbonyl, di C.sub.1-12alkylaminocarbonyl,
C.sub.1-12alkynylaminocarbonyl, C.sub.2-13alkoxyalkylaminocarbonyl
thiophenyl C.sub.1-12alkylaminocarbonyl, benzylaminocarbonyl,
dihydropyrrolylcarbonyl, cycloalkyl C.sub.1-12alkylcarbonyl,
cycloalkenyl C.sub.1-12alkylcarbonyl,
C.sub.2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl,
piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl,
hydroxyaminocarbonyl, hydroC.sub.1-12alkylaminocarbonyl,
hydrazinylcarbonyl, C.sub.1-12alkylformatehydrazinylcarbonyl, or
tetrahydrofuranylC.sub.1-12alkylaminocarbonyl;
[0207] sulfonyl group is tosyl, phenyl sulfonyl, C.sub.1-12alkyl
sulfonyl, C.sub.1-12alkylsulfonylamino, aminosulfonylamino or
halo-phenyl sulfonyl;
[0208] substituted alkoxy is morpholinyl C.sub.1-12alkoxy,
dihalo-C.sub.1-12alkoxy, or piperazinyl C.sub.1-12alkoxy;
[0209] substituted aryloxy is halo-C.sub.6-12aryloxy;
[0210] substituted pyridinyl is halo-pyridinyl, C.sub.1-12alkoxy
pyridinyl, amino pyridinyl, or morpholinyl pyridinyl;
[0211] substituted tetrahydro-carbazolyl is
phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
[0212] These compounds may be prepared by utilizing appropriate
starting component molecules (hereinafter referred to as "component
pieces"). Briefly, in the synthesis of reverse-turn mimetic
structures having Formula (I), the reverse-turn mimetic structures
of Formula (I) may be prepared by sequential coupling of the
individual component pieces either stepwise in solution or by solid
phase synthesis as commonly practiced in solid phase peptide
synthesis, followed by cyclizing to yield the reverse-turn mimetic
structures of this invention. Alternatively, first and second
component pieces are coupled to form a combined first-second
intermediate, if necessary, third and/or fourth component pieces
are coupled to form a combined third-fourth intermediate (or, if
commercially available, a single third intermediate may be used),
the combined first-second intermediate and third-fourth
intermediate (or third intermediate) are then coupled to provide a
first-second-third-fourth intermediate (or first-second-third
intermediate) which is cyclized to yield the reverse-turn mimetic
structures of this invention.
[0213] Specific component pieces and the assembly thereof to
prepare compounds of the present invention are illustrated in FIG.
1. For example, a "first component piece" may have the following
formula S1:
##STR00013##
[0214] wherein R.sub.1 is as defined above, and R is a protective
group suitable for use in peptide synthesis, where this protection
group may be joined to a polymeric support to enable solid-phase
synthesis. Suitable R groups include alkyl groups and, in a
preferred embodiment, R is a methyl group. In FIG. 1, one of the R
groups is a polymeric (solid) support, indicated by "Pol" in the
Figure. Such first component pieces may be readily synthesized by
reductive amination of H.sub.2N--C--R.sub.1 with CH(OR).sub.2--CHO,
or by a displacement reaction between H.sub.2N--C--R.sub.1 and
CH(OR).sub.2--CH.sub.2-LG (wherein LG refers to a leaving group,
e.g., a halogen (Hal) group).
[0215] A "second component piece" may have the following formula
S2:
##STR00014##
where P is an amino protection group suitable for use in peptide
synthesis, L.sub.1 is hydroxyl or a carboxyl-activation group, and
R.sub.2 is as defined above. Preferred protection groups include
t-butyl dimethylsilyl (TBDMS), t-butyloxycarbonyl (BOC),
methyloxycarbonyl (MOC), 9H-fluorenylmethyloxycarbonyl (FMOC), and
allyloxycarbonyl (Alloc). N-Protected amino acids are commercially
available; for example, FMOC amino acids are available from a
variety of sources. In order for the second component piece to be
reactive with the first component piece, L.sub.1 is a
carboxyl-activation group, and the conversion of carboxyl groups to
activated carboxyl groups may be readily achieved by methods known
in the art for the activation of carboxyl groups. Suitable
activated carboxylic acid groups include acid halides where L.sub.1
is a halide such as chloride or bromide, acid anhydrides where
L.sub.1 is an acyl group such as acetyl, reactive esters such as
N-hydroxysuccinimide esters and pentafluorophenyl esters, and other
activated intermediates such as the active intermediate formed in a
coupling reaction using a carbodiimide such as
dicyclohexylcarbodiimide (DCC). Accordingly, commercially available
N-protected amino acids may be converted to carboxylic activated
forms by means known to one of skill in the art.
[0216] In the case of the azido derivative of an amino acid serving
as the second component piece, such compounds may be prepared from
the corresponding amino acid by the reaction disclosed by Zaloom et
al. (J. Org. Chem. 46:5173-76, 1981).
[0217] A "third component piece" of this invention may have the
following formula S3:
##STR00015##
[0218] where R.sub.4, E, and L.sub.1 are as defined above. Suitable
third component pieces are commercially available from a variety of
sources or can be prepared by methods well known in organic
chemistry.
[0219] FIG. 1 illustrates the preparation of compounds of Formula
(I).
[0220] Thus, as illustrated above, the reverse-turn mimetic
compounds of Formula (I) may be synthesized by reacting a first
component piece with a second component piece to yield a combined
first-second intermediate, followed by reacting the combined
first-second intermediate with third component pieces sequentially
to provide a combined first-second-third-fourth intermediate, and
then cyclizing this intermediate to yield the reverse-turn mimetic
structure.
[0221] The syntheses of representative component pieces of this
invention are described in Preparation Examples.
[0222] The reverse-turn mimetic structures of Formula (I) and (II)
may be made by techniques analogous to the modular component
synthesis disclosed above, but with appropriate modifications to
the component pieces.
[0223] The reverse-turn mimetic structures of the present invention
are useful as bioactive agents, such as diagnostic, prophylactic,
and therapeutic agents. For example, the reverse-turn mimetic
structures of the present invention may be used for modulating a
cell signaling transcription factor related peptides in a
warm-blooded animal, by a method comprising administering to the
animal an effective amount of the compound of Formula (I).
[0224] Further, the reverse-turn mimetic structures of the present
invention may also be effective for inhibiting peptide binding to
PTB domains in a warm-blooded animal; for modulating G protein
coupled receptor (GPCR) and ion channel in a warm-blooded animal;
for modulating cytokines in a warm-blooded animal.
[0225] It has been found that the compounds of the Formula (I),
especially compounds of Formula (III) are effective for inhibiting
or treating disorders modulated by Wnt-signaling pathway, such as
cancer.
##STR00016##
[0226] Formula (III) is shown above, wherein each of R.sub.1,
R.sub.4, and R.sub.6 is the same or different and independently an
amino acid side chain moiety or an animo acid side chain
derivative, X.sub.1 may be hydrogen, hydroxyl, or halogen, and
X.sub.2 and X.sub.3 may be independently hydrogen, hydroxyl, or any
groups that may make the compound a prodrug, such as phosphate,
carboxylate, carbamate and substituted amine.
[0227] In certain embodiments of the compounds of Formula
(III),
[0228] R.sub.1 is phenyl, substituted phenyl, pyridinyl,
substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl,
indolyl, substituted indolyl, benzothiazolyl, substituted
benzothiazolyl, benzimidazolyl, substituted benzimidazolyl,
benzothiophenyl, substituted benzothiophenyl, benzodioxolyl,
substituted benzodioxolyl, benzoxazolyl, substituted benzoxazolyl,
benzisoxazolyl, substituted benzisoxazolyl, chromonyl, substituted
chromonyl, tetrahydro-carbazolyl, substituted
tetrahydro-carbazolyl, benzyl or substituted benzyl,
aminocarbonylC.sub.1-6alkyl,
C.sub.1-3alkylthiazolyl-aminocarbonylC.sub.1-6alkyl,
dibenzofuranyl, acetylenyl, or styrenyl;
[0229] R.sub.4 is C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl
or perfluoroC.sub.1-6alkyl;
[0230] R.sub.6 is C.sub.6-12aryl or substituted C.sub.6-12aryl
having one or more substituents independently selected from the
group consisting of: halogen; hydroxyl; cyano; C.sub.1-6alkyl; and
C.sub.1-6alkoxy; or C.sub.5-12heterocyclyl or substituted
C.sub.5-12heterocyclyl having one or more substituents
independently selected from: halogen, hydroxyl, cyano,
C.sub.1-6alkyl, and C.sub.1-6alkoxy;
[0231] X.sub.1 is hydrogen, hydroxyl or halogen; and
[0232] each of X.sub.2 and X.sub.3 is independently hydrogen,
hydroxyl, phosphate, dimethylaminoacetate,
(2-dimethylamino-ethyl)-carbamate, diethyl-phosphono-acetamido or
halogen.
[0233] In certain embodiment of the compounds described in the
preceding paragraph,
[0234] R.sub.1 is selected from the group consisting of:
[0235] substituted phenyl having one or more substituents
independently selected from: halogen, nitro, cyano, hydroxyl,
C.sub.1-12alkoxy, substituted C.sub.1-12alkoxy, C.sub.1-12alkyl,
carbonyl, carboxy, acetyl, C.sub.1-12alkylthio, C.sub.6-12arylthio,
thiophenyl, sulfonyl, C.sub.6-12aryloxy, substituted
C.sub.6-12aryloxy, indanyloxy, amino,
aldoaminoC.sub.1-12alkylbenzylamino, amide,
C.sub.1-12alkyl-sulfonic acid, C.sub.1-12alkyl phosphoric acid,
phenyl, substituted phenyl, pyrrolidinyl, piperazinyl, pyridinyl,
substituted pyridinyl, tetrazolyl, thiazolyl, pyridinone, and
imidazolyl;
[0236] substituted pyridinyl having one or more substituents
independently selected from: halogen, cycloalkyl, phenyl,
substituted phenyl, pyrrolidinyl-piperidinyl, pyridinyl, carbonyl,
amide, and carboxy;
[0237] substituted pyrimidinyl having one or more substituents
independently selected from phenyl and amino:
[0238] substituted indolyl having one or more substituents
independently selected from: phenyl, substituted phenyl,
substituted benzyl, pyridinyl, sulfonyl, acetyl, acyl, carbonyl,
C.sub.1-12alkyl, acyloxy C.sub.1-12alkyl, C.sub.1-12alkoxy,
halogen, monoxide, and cyano;
[0239] substituted benzimidazolyl having one or more substituents
independently selected from: carbonyl, monoxide, thio,
perfluoroC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, and
[0240] substituted benzothiophenyl having one or more substituents
independently selected from: nitro, amino, C.sub.1-4alkylamino,
bisbenzylamino, amide, halogen, benzylamino, sulfonyl, dioxo,
aldoamino, and carbonyl;
[0241] substituted benzodioxolyl having one or more substituents
independently selected from: nitro and halogen;
[0242] substituted benzoxazolyl having one or more substituents
independently selected from: monoxide, and thio;
[0243] substituted benzisoxazolyl having one or more substituents
independently selected from: amino;
[0244] substituted chromonyl having one or more substituents
independently selected from: phenyl; and
[0245] substituted tetrahydro-carbazolyl having one or more
substituents independently selected from: sulfonyl;
[0246] R.sub.4 is C.sub.1-3alkyl or allyl; and
[0247] R.sub.6 is phenyl or substituted phenyl having one or more
substituents independently selected from: halogen, hydroxyl, cyano,
C.sub.1-6alkyl and C.sub.1-6alkoxy; or pyridyl or substituted
pyridyl having one or more substituents independently selected
from: halogen, hydroxyl, cyano, C.sub.1-6alkyl and
C.sub.1-6alkoxy.
[0248] In certain embodiment of the compounds described in the
preceding paragraph,
[0249] substituted phenyl is halo-phenyl, cyano phenyl,
C.sub.1-12alkoxy phenyl, hydroxy phenyl, carboxy phenyl, acetamide
phenyl, aminocarbonyl phenyl, amino phenyl, alkylsulfonyl phenyl,
or alkylthio phenyl;
[0250] substituted benzyl is nitro-benzyl, or amino-benzyl;
[0251] amide group is C.sub.1-6alkylamide, carbamide,
C.sub.1-6alkylcarbamide, C.sub.1-6alkylcarbamate,
[0252] C.sub.1-6alkylalkoxycarbamate, formamide,
C.sub.1-6alkylformamide, carbamoylurea, or acetamide;
[0253] carbonyl group is cycloalkylcarbonyl,
C.sub.1-12alkoxycarbonyl, morpholinylcarbonyl, aminocarbonyl,
C.sub.1-12alkylaminocarbonyl, di C.sub.1-12alkylaminocarbonyl,
C.sub.1-12alkynylaminocarbonyl, C.sub.2-13alkoxyalkylaminocarbonyl
thiophenyl C.sub.1-12alkylaminocarbonyl, benzylaminocarbonyl,
dihydropyrrolylcarbonyl, cycloalkyl C.sub.1-12alkylcarbonyl,
cycloalkenyl C.sub.1-12alkylcarbonyl,
C.sub.2-13alkoxyalkylcarbonyl, imidazolylaminocarbonyl,
piperidinylcarbonyl, pyrrolidinylcarbonyl, alkoxyaminocarbonyl,
hydroxyaminocarbonyl, hydroC.sub.1-12alkylaminocarbonyl,
hydrazinylcarbonyl, C.sub.1-12alkylformatehydrazinylcarbonyl, or
tetrahydrofuranylC.sub.1-12alkylaminocarbonyl;
[0254] sulfonyl group is tosyl, phenyl sulfonyl, C.sub.1-12alkyl
sulfonyl, C.sub.1-12alkylsulfonylamino, aminosulfonylamino or
halo-phenyl sulfonyl;
[0255] substituted alkoxy is morpholinyl C.sub.1-12alkoxy,
dihalo-C.sub.1-12alkoxy, or piperazinyl C.sub.1-12alkoxy;
[0256] substituted aryloxy is halo-C.sub.6-12aryloxy;
[0257] substituted pyridinyl is halo-pyridinyl, C.sub.1-12alkoxy
pyridinyl, amino pyridinyl, or morpholinyl pyridinyl; or
[0258] substituted tetrahydro-carbazolyl is
phenylsulfonyl-6,7,8,9-tetrahydro-5H-carbazolyl.
[0259] In another aspect of this invention, prodrugs derived from
compounds having general Formula (I) are disclosed. The prodrugs
generally increase aqueous solubility and thus bioavailability of
compounds having general Formula (I). In certain embodiments, the
prodrugs of the present invention have the following general
Formula (IV):
(III)-R.sub.7 (IV)
[0260] wherein one of R.sub.1, R.sub.4, R.sub.6, X.sub.1, X.sub.2,
and X.sub.3 is linked to R.sub.7 via Y, wherein:
[0261] Y is an oxygen, sulfur, or nitrogen in R.sub.1, R.sub.4, or
R.sub.6, or an oxygen in X.sub.1, X.sub.2, or X.sub.3; and
[0262] R.sub.7 is hydroxyalkyl, glycosyl,
phosphoryloxymethyloxycarbonyl, substituted or =substituted
piperidine carbonyloxy, or a salt thereof; or Y--R.sub.7 is an
amino acid residue, a combination of amino acid residues,
phosphate, hemimalate, hemisuccinate, dimethylaminoalkylcarbamate,
dimethylaminoacetate, or a salt thereof; and
[0263] when not linked to R.sub.7: R.sub.1, R.sub.4, R.sub.6,
X.sub.1, X.sub.2, and X.sub.3 are defined as they are in Formula
(III).
[0264] In another aspect of this invention, libraries containing
reverse-turn mimetic structures of the present invention are
disclosed. Once assembled, the libraries of the present invention
may be screened to identify individual members having bioactivity.
Such screening of the libraries for bioactive members may involve;
for example, evaluating the binding activity of the members of the
library or evaluating the effect the library members have on a
functional assay. Screening is normally accomplished by contacting
the library members (or a subset of library members) with a target
of interest, such as, for example, an antibody, an enzyme, a
receptor or a cell line. Library members which are capable of
interacting with the target of interest are referred to herein as
"bioactive library members" or "bioactive mimetics". For example, a
bioactive mimetic may be a library member which is capable of
binding to an antibody or receptor, or which is capable of
inhibiting an enzyme, or which is capable of eliciting or
antagonizing a functional response associated, for example, with a
cell line. In other words, the screening of the libraries of the
present invention determines which library members are capable of
interacting with one or more biological targets of interest.
Furthermore, when interaction does occur, the bioactive mimetic (or
mimetics) may then be identified from the library members. The
identification of a single (or limited number) of bioactive
mimetic(s) from the library yields reverse-turn mimetic structures
which are themselves biologically active, and thus are useful as
diagnostic, prophylactic or therapeutic agents, and may further be
used to significantly advance identification of lead compounds in
these fields.
[0265] Synthesis of the peptide mimetics of the library of the
present invention may be accomplished using known peptide synthesis
techniques, in combination with the first, second and third
component pieces of this invention. More specifically, any amino
acid sequence may be added to the N-terminal and/or C-terminal of
the conformationally constrained reverse-turn mimetic. To this end,
the mimetics may be synthesized on a solid support (such as PAM
resin) by known techniques (see, e.g., John M. Stewart and Janis D.
Young, Solid Phase Peptide Synthesis, 1984, Pierce Chemical Comp.,
Rockford, Ill.) or on a silyl-linked resin by alcohol attachment
(see Randolph et al., J. Am. Chem. Soc. 117:5712-14, 1995).
[0266] In addition, a combination of both solution and solid phase
synthesis techniques may be utilized to synthesize the peptide
mimetics of this invention. For example, a solid support may be
utilized to synthesize the linear peptide sequence up to the point
that the conformationally constrained reverse-turn is added to the
sequence. A suitable conformationally constrained reverse-turn
mimetic structure which has been previously synthesized by solution
synthesis techniques may then be added as the next "amino acid" to
the solid phase synthesis (i.e., the conformationally constrained
reverse-turn mimetic, which has both an N-terminus and a
C-terminus, may be utilized as the next amino acid to be added to
the linear peptide). Upon incorporation of the conformationally
constrained reverse-turn mimetic structures into the sequence,
additional amino acids may then be added to complete the peptide
bound to the solid support. Alternatively, the linear N-terminus
and C-terminus protected peptide sequences may be synthesized on a
solid support, removed from the support, and then coupled to the
conformationally constrained reverse-turn mimetic structures in
solution using known solution coupling techniques.
[0267] In one aspect of this invention, methods for constructing
the libraries are disclosed. Traditional combinatorial chemistry
techniques (see, e.g., Gallop et al., J. Med. Chem. 37:1233-1251,
1994) permit a vast number of compounds to be rapidly prepared by
the sequential combination of reagents to a basic molecular
scaffold. Combinatorial techniques have been used to construct
peptide libraries derived from the naturally occurring amino acids.
For example, by taking 20 mixtures of 20 suitably protected and
different amino acids and coupling each with one of the 20 amino
acids, a library of 400 (i.e., 20.sup.2) dipeptides is created.
Repeating the procedure seven times results in the preparation of a
peptide library comprised of about 26 billion (i.e., 20.sup.8)
octapeptides.
[0268] Specifically, synthesis of the peptide mimetics of the
library of the present invention may be accomplished using known
peptide synthesis techniques, for example, the General Scheme of
Reverse-Turn Mimetic Library, as follows:
##STR00017##
Synthesis of the peptide mimetics of the libraries of the present
invention was accomplished using a FlexChem Reactor Block which has
96 well plates by known techniques. In the above scheme `Pol`
represents a bromoacetal resin (Advanced ChemTech) and detailed
procedure is illustrated below:
[0269] Step 1
[0270] A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of
R.sub.i-amine in DMSO (1.4 mL) were placed in a Robbins block
(FlexChem) having 96 well plates. The reaction mixture was shaken
at 60.degree. C. using a rotating oven [Robbins Scientific] for 12
hours. The resin was washed with DMF, MeOH, and then DCM
[0271] Step 2
[0272] A solution of commercially available
Fmoc-NH--CH(R.sub.2)--COOH (4 equiv.), PyBob (4 equiv.), HOAt (4
equiv.), and DIEA (12 equiv.) in DMF was added to the resin. After
the reaction mixture was shaken for 12 hours at room temperature,
the resin was washed with DMF, MeOH, and then DCM.
[0273] Step 3
[0274] To the resin swollen by DMF before reaction was added 25%
piperidine in DMF and the reaction mixture was shaken for 30 min at
room temperature. This deprotection step was repeated again and the
resin was washed with DMF, Methanol, and then DCM. A solution of
hydrazine acid (4 equiv.), HOBt (4 equiv.), and DIC (4 equiv.) in
DMF was added to the resin and the reaction mixture was shaken for
12 hours at room temperature. The resin was washed with DMF, MeOH,
and then DCM.
[0275] Step 4
[0276] The resin obtained in Step 3 was treated with formic acid
(1.2 mL each well) for 18 hours at room temperature. After the
resin was removed by filtration, the filtrate was condensed under a
reduced pressure using SpeedVac [SAVANT] to give the product as
oil. The product was diluted with 50% water/acetonitrile and then
lyophilized after freezing.
[0277] To generate these block libraries the key intermediate
hydrazine acids were synthesized according to the procedure
illustrated in Preparation Example 1.
[0278] Table 2 shows the compounds which were prepared according to
the present invention, of which representative preparation is given
in Preparation Examples.
TABLE-US-00002 TABLE 2 REVERSE TURN MIMETICS LIBRARY M.W. NO
Structure Formula M + H 1 ##STR00018## 599.66 C30H29N7O5S 600 2
##STR00019## 597.69 C31H31N7O4S 598 3 ##STR00020## 570.66
C30H30N6O4S 571 4 ##STR00021## 610.73 C33H34N6O4S 611 5
##STR00022## 596.70 C31H32N8O3S 597 6 ##STR00023## 623.72
C33H33N7O4S 624 7 ##STR00024## 637.75 C34H35N7O4S 638 8
##STR00025## 653.75 C34H35N7O5S 654 9 ##STR00026## 595.71
C32H33N7O3S 596 10 ##STR00027## 624.71 C32H32N8O4S 625 11
##STR00028## 614.71 C32H34N6O5S 615 12 ##STR00029## 644.74
C33H36N6O6S 645 13 ##STR00030## 673.80 C33H35N7O5S2 674 14
##STR00031## 638.74 C33H34N8O4S 639 15 ##STR00032## 628.74
C33H36N6O5S 629 16 ##STR00033## 626.73 C33H34N6O5S 627 17
##STR00034## 681.76 C34H35N9O5S 682 18 ##STR00035## 624.71
C33H32N6O5S 625 19 ##STR00036## 623.72 C33H33N7O4S 624 20
##STR00037## 640.71 C33H32N6O6S 641 21 ##STR00038## 639.72
C33H33N7O5S 640 22 ##STR00039## 623.72 C33H33N7O4S 624 23
##STR00040## 637.75 C34H35N7O4S 638 24 ##STR00041## 610.73
C33H34N6O4S 611 25 ##STR00042## 653.75 C34H35N7O6S 654 26
##STR00043## 653.75 C34H35N7O5S 654 27 ##STR00044## 639.72
C33H33N7O5S 640 28 ##STR00045## 619.74 C34H33N7O3S 620 29
##STR00046## 638.74 C33H34N8O4S 639 30 ##STR00047## 652.77
C34H36N8O4S 653 31 ##STR00048## 653.75 C34H35N7O5S 654 32
##STR00049## 654.74 C33H34N8O5S 655 33 ##STR00050## 667.78
C35H37N7O5S 668 34 ##STR00051## 609.74 C33H35N7O3S 610 35
##STR00052## 637.75 C34H35N7O4S 638 36 ##STR00053## 609.74
C33H35N7O3S 610 37 ##STR00054## 637.75 C34H35N7O4S 638 38
##STR00055## 635.74 C34H33N7O4S 636 39 ##STR00056## 620.72
C33H32N8O3S 621 40 ##STR00057## 631.14 C32H31ClN6O4S 632 41
##STR00058## 675.60 C32H31BrN6O4S 676 42 ##STR00059## 674.79
C32H34N8O5S2 675 43 ##STR00060## 722.60 C32H31IN6O4S 723 44
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C33H31N7O5S 638 55 ##STR00072## 610.73 C32H34N8O3S 611 56
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585 100 ##STR00117## 676.74 C32H36N8O7S 678 101 ##STR00118## 612.68
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857.78 C39H38N7Na2O9PS 859 228 ##STR00245## 692.80 C39H44N6O6 694
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C31H33N7O5 585
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##STR00460## 617.73 C31H35N7O5S 619 444 ##STR00461## 631.76
C32H37N7O5S 633 445 ##STR00462## 618.72 C30H34N8O5S 620 446
##STR00463## 522.62 D488C26H30N6O4S 524 447 ##STR00464## 572.68
C30H32N6O4S 574 448 ##STR00465## 572.68 C30H32N6O4S 574 449
##STR00466## 573.66 C30H31N5O5S 575 450 ##STR00467## 598.72
C32H34N6O4S 600 451 ##STR00468## 587.69 C31H33N5O5S 589 452
##STR00469## 574.65 C29H30N6O5S 576 453 ##STR00470## 574.65
C29H30N6O5S 576 454 ##STR00471## 574.65 C29H30N6O5S 576 455
##STR00472## 586.71 C31H34N6O4S 588 456 ##STR00473## 557.66
C30H31N5O4S 559 457 ##STR00474## 571.69 C31H33N5O4S 573 458
##STR00475## 585.72 C32H35N5O4S 587 459 ##STR00476## 599.74
C33H37N5O4S 601 460 ##STR00477## 529.65 C29H31N5O3S 531 461
##STR00478## 543.68 C30H33N5O3S 545 462 ##STR00479## 557.71
C31H35N5O3S 559 463 ##STR00480## 571.73 C32H37N5O3S 573 464
##STR00481## 615.75 C32H37N7O4S 617 465 ##STR00482## 615.70
C31H33N7O5S 617 466 ##STR00483## 614.76 C33H38N6O4S 616 467
##STR00484## 614.72 C32H34N6O5S 616 468 ##STR00485## 600.78
C33H40N6O3S 602 469 ##STR00486## 600.73 C32H36N6O4S 602 470
##STR00487## 657.78 C34H39N7O5S 659 471 ##STR00488## 670.83
C35H42N8O4S 672 472 ##STR00489## 586.71 C31H34N6O4S 588 473
##STR00490## 628.74 C33H36N6O5S 630 474 ##STR00491## 641.78
C34H39N7O4S 643 475 ##STR00492## 597.73 C33H35N5O4S 599 476
##STR00493## 599.70 C32H33N5O5S 601 477 ##STR00494## 585.72
C32H35N5O4S 587 478 ##STR00495## 583.70 C32H33N5O4S 585 479
##STR00496## 569.72 C32H35N5O3S 571 480 ##STR00497## 584.69
C31H32N6O4S 586 481 ##STR00498## 612.74 C33H36N6O4S 614 482
##STR00499## 626.77 C34H38N6O4S 628 483 ##STR00500## 615.75
C32H37N7O4S 617 484 ##STR00501## 629.77 C33H39N7O4S 631 485
##STR00502## 629.73 C32H35N7O5S 631 486 ##STR00503## 611.72
C32H33N7O4S 613 487 ##STR00504## 630.76 C33H38N6O5S 632 488
##STR00505## 616.73 C32H36N6O5S 618
[0279] Belows are NMR data of some of the compounds prepared
according to the above procedure:
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-((1-(3-nitrobenzyl)-1H-in-
dol-7-yl)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6-
H)-carboxamide
[0280] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.06 (d, J=9.0 Hz,
1H), .delta. 7.65 (d, J=6.0 Hz, 2H), .delta. 7.44 (t, J=6.0 Hz,
1H), 7.35.about.7.20 (m, 6H), .delta. 7.11.about.7.05 (m, 2H),
.delta. 6.95.about.6.87 (m, 3H), .delta. 6.66.about.6.62 (m, 4H),
.delta. 5.51.about.5.30 (m, 3H), .delta. 5.02.about.4.94 (m, 2H),
.delta. 4.61 (d, J=18.0 Hz, 1H), .delta. 4.44.about.4.25 (m, 3H),
.delta. 3.42.about.2.99 (m, 8H)
(6S,9aS)-2-allyl-8-((1-(3-aminobenzyl)-1H-indol-7-yl)methyl)-N-benzyl-6-(4-
-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6-
H)-carboxamide
[0281] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.63.about.7.58
(m, 1H), .delta. 7.38.about.7.20 (m, 5H), .delta. 7.05.about.6.94
(m, 4H), .delta. 6.87 (d, J=6.0 Hz, 1H), .delta. 6.67.about.6.57
(m, 3H), .delta. 6.45 (d, J=6.0 Hz, 1H), .delta. 6.19 (d, J=9.0 Hz,
2H), .delta. 5.54.about.5.38 (m, 3H), 5.32.about.5.24 (m, 1H),
.delta. 5.11 (t, J=6.0 Hz, 1H), .delta. 5.00 (d, J=12.0 Hz, 1H),
.delta. 4.77.about.4.65 (m, 2H), .delta. 4.44.about.4.26 (m, 2H),
.delta. 3.39.about.3.17 (m, 5H), .delta. 2.94 (d, J=9.0 Hz, 2H)
(6S,9aR)
2-allyl-8-(2,4-difluoro-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-he-
xahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0282] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.25.about.7.36
(m, 7H), 7.04 (d, J=8.4 Hz, 2H), 6.62-6.89 (m, 6H), 5.68-5.82 (m,
3H), 5.16-5.24 (m, 2H), 4.42 (d, J=6.0 Hz, 2H), 4.01-4.06 (m, 1H),
3.38-3.71 (m, 8H), 3.20 (dd, J=3.6, 11.4 Hz, 2H), 2.80-3.02 (m,
4H), 2.46-2.52 (m, 1H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(2,3,4-trimethoxy-benzyl-
)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0283] .sup.1H NMR (CDCl.sub.3): .delta. 7.404.about.7.245 (m, 5H),
.delta. 7.001.about.6.973 (d, J=8.4 Hz, 2H), 6.958.about.6.930 (d,
J=8.4 Hz, 1H), 7.742.about.7.701 (t, J=6.0 Hz, 1H),
6.675.about.6.647 (d, J=8.4 Hz, 2H), 6.647.about.6.619 (d, J=8.4
Hz, 2H), 5.695.about.5.561 (dt, J=6.6 Hz, J=16.8 Hz, 1H),
5.534.about.5.520 (dd, J=4.2 Hz, J=10.8 Hz, 1H), 5.390.about.5.340
(dd, J=4.8 Hz, J=10.2 Hz, 1H), 5.284.about.5.248 (t, J=5.4 Hz, 1H),
5.175.about.5.140 (d, J=10.5 Hz, 1H), 5.080.about.5.022 (d, J=17.4
Hz, 1H), 4.882.about.4.834 (d, J=17.4 Hz, 1H), 4.486.about.4.306
(dt, J=6.0 Hz, J=15.0 Hz, 2H), 3.875 (s, 3H), 3.546.about.3.253 (m,
8H)
(6S,9aS)
2-allyl-8-(3,4-dimethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-h-
exahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0284] .sup.1H NMR (CDCl.sub.3): .delta. 7.395.about.7.233 (m, 6H),
.delta. 6.8314.682 (m, 4H), 6.985.about.6.958 (d, J=8.1 Hz, 2H),
6.637.about.6.610 (d, J=8.1 Hz, 2H), 5.678.about.5.545 (dt, J=6.3
Hz, J=16.8 Hz, 1H), 5.454.about.5.405 (dd, J=3.9 Hz, J=10.5 Hz,
1H), 5.323.about.5.286 (d, J=5.7 Hz, 1H), 5.162.about.5.127 (d,
J=10.5 Hz, 1H), 5.028.about.4.971 (d, J=16.8 Hz, 1H),
4.916.about.4.868 (d, J=14.4 Hz, 1H), 4.467.about.4.294 (dt, J=6.3
Hz, J=15.0 Hz, 2H), 5.390.about.5.340 (dd, J=4.8 Hz, J=10.2 Hz,
1H), 5.284.about.5.248 (t, J=5.4 Hz, 1H), 4.269.about.4.221 (d,
J=14.4 Hz, 1H), 3.864 (s, 6H), 3.499.about.3.223 (m, 7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-[1-(toluene-4-sulfonyl)--
1H-indol-7-ylmethyl]-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0285] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.66 (d, J=4.0
Hz, 1H), 7.31-7.48 (m, 6H), 7.16-7.23 (m, 4H), 7.03 (d, J=8.4 Hz,
2H), 6.90 (d, J=7.8 Hz, 1H), 6.67-6.70 (m, 3H), 5.49-5.61 (m, 2H),
5.31-5.47 (m, 2H), 4.92-5.14 (m, 3H), 4.26-4.44 (m, 2H), 3.29-3.50
(m, 6H), 2.32 (s, 3H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(1H-indol-7-ylmethyl)-4,7-dioxo-he-
xahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0286] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.95 (s, 1H), 7.63
(d, J=8.1 Hz, 1H), 7.28-7.37 (m, 4H), 7.23-7.25 (m, 1H), 6.90-7.00
(m, 4H), 6.67 (m, 1H), 6.55-6.58 (m, 3H), 5.60 (m, 1H), 5.12-.5.28
(m, 4H), 4.93 (d, J=17.1 Hz, 1H), 4.32-4.41 (m, 3H), 3.21-3.39 (m,
8H)
(6S,9aS)
2-allyl-7-(2-fluoro-4-methoxy-benzyl)-5-(4-hydroxy-benzyl)-4,6-di-
oxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid
benzylamide
[0287] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.39.about.7.24
(m, 5H), 6.96 (d, J=8.3 Hz, 2H), 6.79 (s, 1H), 6.73.about.6.67 (m,
2H), 6.62.about.6.58 (m, 3H), 5.70.about.5.57 (m, 1H), 5.45 (dd,
J=10.7 Hz 4.0 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 5.18 (d, J=10.3 Hz,
1H), 5.08 (d, J=17.1 Hz, 1H), 4.80 (d, J=5.6 Hz, 1H),
4.48.about.4.30 (m, 3H), 3.79 (s, 3H), 3.54.about.3.25 (m, 8H)
(6S,9aS)-2-allyl-N-benzyl-8-(4-butoxybenzyl)-6-(4-hydroxy-benzyl)-4,7-diox-
o-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0288] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.73.about.7.23
(m, 6H), .delta. 7.12 (d, J=9.0 Hz, 2H), .delta. 6.98 (d, J=9.0 Hz,
2H), .delta. 6.86 (d, J=9.0 Hz, 2H), .delta. 6.71 (t, J=6.0 Hz,
1H), .delta. 6.65 (d, J=9.0 Hz, 2H), .delta. 5.67.about.5.48 (m,
2H), .delta. 5.32 (t, J=6.0 Hz, 1H), .delta. 5.13 (d, J=12.0 Hz,
2H), .delta. 5.00 (d, J=3.0 Hz, 1H), .delta. 4.93 (s, 1H), .delta.
4.46.about.4.30 (m, 2H), .delta. 3.19 (d, J=18.0 Hz, 1H), .delta.
3.93 (t, J=9.0 Hz, 2H), .delta. 3.44.about.3.21 (m, 7H), .delta.
1.78.about.1.71 (m, 2H), .delta. 1.54.about.1.41 (m, 2H), .delta.
0.96 (t, J=15.0 Hz, 3H)
(6S,9aS)-2-allyl-N-benzyl-8-(3-chloro-4-methoxybenzyl)-6-(4-hydroxy-benzyl-
)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0289] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.39.about.7.23
(m, 6H), .delta. 7.09 (d, J=9.0 Hz, 2H), .delta. 6.98 (d, J=9.0 Hz,
2H), .delta. 6.89 (d, J=9.0 Hz, 1H), .delta. 6.73.about.6.53 (m,
3H), .delta. 5.67.about.5.58 (m, 1H), .delta. 5.38 (dd, J=3.0 Hz,
J=9.0 Hz, 1H), .delta. 5.21 (t, J=6.0 Hz, 1H), .delta. 5.17 (d,
J=12.0 Hz, 1H), .delta. 5.03 (d, J=15.0 Hz, 1H), .delta. 4.76 (dd,
J=3.0 Hz, J=18.0 Hz, 1H), .delta. 4.45.about.4.29 (m, 3H), .delta.
3.88 (s, 3H), 3.49.about.3.18 (m, 8H)
(6S,9aS)-2-allyl-N-benzyl-8-(3-fluoro-4-methoxybenzyl)-6-(4-hydroxy-benzyl-
)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0290] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.39.about.7.23
(m, 6H), .delta. 7.09 (d, J=9.0 Hz, 2H), .delta. 6.98 (d, J=9.0 Hz,
2H), .delta. 6.89 (d, J=9.0 Hz, 1H), .delta. 6.73.about.6.53 (m,
3H), .delta. 5.67.about.5.58 (m, 1H), .delta. 5.38 (dd, J=3.0 Hz,
J=9.0 Hz, 1H), .delta. 5.21 (t, J=6.0 Hz, 1H), .delta. 5.17 (d,
J=12.0 Hz, 1H), .delta. 5.03 (d, J=15.0 Hz, 1H), .delta. 4.76 (dd,
J=3.0 Hz, J=18.0 Hz, 1H), .delta. 4.45.about.4.29 (m, 3H), .delta.
3.88 (s, 3H), 3.49.about.3.18 (m, 8H)
(6S,9aS)
2-allyl-7-(4-allyloxy-benzyl)-5-(4-hydroxy-benzyl)-4,6-dioxo-octa-
hydro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
[0291] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.39.about.7.23
(m, 4H), 7.15 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.89 (brs,
OH), 6.88 (d, J=8.4 Hz, 2H), 6.70 (t, J=6.0 Hz, NH), 6.63 (d, J=8.4
Hz, 2H), 6.10.about.5.97 (m, 1H), 5.67.about.5.53 (m, 1H),
5.48.about.5.26 (m, 4H), 5.14 (d, J=10.3 Hz, 1H), 4.98 (d, J=17.2
Hz, 1H), 4.90 (d, J=14.4 Hz, 1H), 4.52 (d, J=5.3 Hz, 2H),
4.46.about.4.29 (m, 2H), 4.25 (d, J=4.4 Hz, 1H), 3.49.about.3.20
(m, 8H)
(6S,9aS)
2-allyl-8-(2-bromo-pyridin-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-d-
ioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0292] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.29-3.40 (m,
4H), 3.50-3.59 (m, 4H), 4.39 (qd, J=5.9 Hz, 2H), 4.61 (d, J=15.8
Hz, 1H), 4.85 (d, J=15.8 Hz, 1H), 5.16 (d, 1H), 5.21 (d, 1H), 5.32
(t, J=5.1 Hz, 1H), 5.48 (dd, J=3.7 Hz, J=10.6 Hz, 1H), 5.60-5.69
(m, 1H), 6.68 (d, J=8.3 Hz, 2H), 6.73 (t, J=5.9 Hz, NH), 6.94 (d,
J=8.3 Hz, 2H), 7.07 (brs, OH), 7.23-7.39 (m, 7H), 8.30 (d, J=2.9
Hz, 1H)
(6S,9aS)
2-allyl-8-(3-bromo-4-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dio-
xo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0293] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.17 (dd, J=4.1
Hz, J=11.7 Hz, 1H), 3.26-3.46 (m, 7H), 3.87 (s, 3H), 4.28-4.35 (m,
2H), 4.43 (dd, J=5.9 Hz, J=14.8 Hz, 1H), 4.73 (d, J=15 Hz, 1H),
5.05 (d, J=15 Hz, 1H), 5.29 (t, J=5.6 Hz, 1H), 5.34 (dd, J=4 Hz,
J=10.6 Hz, 1H), 5.57-5.62 (m, 1H), 6.53 (s, OH), 6.61 (d, J=8.4 Hz,
1H), 6.69 (t, J=6 Hz, NH), 6.83 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4
Hz, 2H), 7.11 (dd, J=2 Hz, J=8.4 Hz, 1H), 7.28-7.38 (m, 5H), 7.44
(d, J=2.1 Hz, 1H)
(6S,9aS)
2-allyl-8-(4-tert-butyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-he-
xahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0294] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 1.3 (s, 9H),
3.19-3.44 (m, 8H), 4.26-4.36 (m, 2H), 4.39 (dd, J=5.9 Hz, J=14.9
Hz, 1H), 4.88 (d, J=14.9 Hz, 1H), 5.12 (d, J=10.3 Hz, 1H), 5.32 (t,
J=5.8 Hz, 1H), 5.45 (dd, J=4.1 Hz, J=10.7 Hz, 1H), 5.55-5.64 (m,
1H), 6.13 (s, OH), 6.62 (d, J=8.4 Hz, 2H), 6.72 (t, J=6 Hz, NH),
7.01 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.29-7.40 (m,
7H)
(6S,9aS)
2-allyl-8-[4-fluoro-3-(2-morpholin-4-yl-ethoxy)-benzyl]-6-(4-hydr-
oxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxyli-
c acid benzylamide
[0295] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 207-2.73 (m, 2H),
2.80-2.94 (m, 4H), 3.29-3.35 (m, 2H), 3.42-3.55 (m, 5H), 3.57 (d,
J=16.9 Hz, 1H), 3.74-3.87 (m, 5H), 4.05-4.08 (m, 1H), 4.16 (dd,
J=5.4 Hz, 1H), 4.22-4.26 (m, 1H), 4.43 (dd, J=6.7 Hz, 1H), 4.81
(dd, J=3 Hz, J=10.5 Hz, 1H), 5.17-5.21 (m, 3H), 5.41 (d, J=15.4 Hz,
1H), 5.64-5.68 (ddd. 1H), 6.47 (d, J=6.6 Hz, 1H), 6.58 (t, J=6.0
Hz, NH), 6.63 (d, J=7.6 Hz, 2H), 6.84 (d, J=7.6 Hz, 2H), 7.01 (dd,
J=8.3 Hz, 1H), 7.23-7.26 (m, 2H), 7.30 (t, J=5.5 Hz, 1H), 7.39 (t,
J=5.5 Hz, 2H)
(6S,9aS)-2-allyl-N-benzyl-8-(4-ethoxybenzyl)-6-(4-hydroxy-benzyl)-4,7-diox-
o-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0296] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.40.about.7.23
(m, 4H), .delta. 7.15 (d, J=9.0 Hz, 2H), .delta. 6.98 (d, J=6.0 Hz,
2H), .delta. 6.85 (d, J=6.0 Hz, 2H), .delta. 6.69 (t, J=6.0 Hz,
1H), .delta. 6.64.about.6.61 (m, 2H), .delta. 5.65.about.5.58 (m,
1H), .delta. 5.45 (dd, J=3.0 Hz, J=9.0 Hz, 1H), .delta.
5.32.about.5.29 (m, 1H), .delta. 5.14 (d, J=9.0 Hz, 1H), .delta.
5.01.about.4.86 (m, 2H), .delta. 4.47.about.4.23 (m, 3H), .delta.
4.02 (q, J=15.0 Hz, 2H), .delta. 3.49.about.3.19 (m, 7H), .delta.
1.40 (t, J=6.0 Hz, 3H)
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-(pentyloxy)b-
enzyl)-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0297] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.39.about.7.23
(m, 4H), .delta. 7.15 (d, J=9.0 Hz, 2H), .delta. 6.98 (d, J=6.0 Hz,
2H), .delta. 6.86 (d, J=9.0 Hz, 2H), .delta. 6.69 (t, J=6.0 Hz,
1H), .delta. 6.63 (d, J=9.0 Hz, 2H), .delta. 5.65.about.5.55 (m,
1H), .delta. 5.45 (dd, 3.0 Hz, J=9.0 Hz, 1H), 65.30 (t, J=6.0 Hz,
1H), 65.14 (d, J=9.0 Hz, 1H), .delta. 5.01.about.4.88 (m, 2H),
.delta. 4.47.about.4.21 (m, 3H), .delta. 3.93 (t, J=6.0 Hz, 2H),
.delta. 3.44.about.3.19 (m, 7H), .delta. 1.82.about.1.73 (m, 2H),
.delta. 1.46.about.1.34 (m, 4H), .delta. 0.93 (t, J=6.0 Hz, 3H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-propoxy-benzyl)-hexah-
ydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0298] .sup.1H NMR (CDCl.sub.3): .delta. 7.390.about.7.227 (m, 5H),
7.156.about.7.127 (d, J=8.7 Hz, 2H), 6.989.about.6.961 (d, J=8.4
Hz, 2H), 6.868.about.6.840 (d, J=8.4 Hz, 2H), 6.717.about.6.677 (t,
J=6.0 Hz, 1H), 6.640.about.6.612 (d, J=8.4 Hz, 2H),
5.667.about.5.533 (dt, J=6.6 Hz, J=12.6 Hz, 1H), 5.460.about.5.412
(dd, J=3.9 Hz, J=10.5 Hz, 1H), 5.321.about.5.283 (t, J=11.4 Hz,
1H), 5.010.about.4.953 (d, J=17.1 Hz, 1H), 4.910.about.4.862 (d,
J=14.4 Hz, 1H), 4.460.about.3.876 (dd, J=6.6 Hz, J=6.6 Hz, 2H),
3.443.about.3.204 (m, 7H), 1.827.about.1.734 (m, 4H),
1.048.about.0.999 (t, J=7.2 Hz, 3H)
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-phenethyl-octahydro-pyri-
do[3,4-c]pyridazine-1-carboxylic acid benzylamide
[0299] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.40.about.7.17
(m, 10H), 6.95 (d, J=8.4 Hz, 2H), 6.67 (t, J=4.0 Hz, NH), 6.62 (d,
J=8.5 Hz, 2H), 6.38 (s, OH), 5.67.about.5.54 (m, 1H),
5.28.about.5.07 (m, 4H), 4.46.about.4.29 (m, 2H), 3.83.about.3.74
(m, 1H), 3.49.about.3.10 (m, 9H), 3.04.about.2.78 (m, 2H)
(6S,9aS)-8-((3-acetyl-1-tosyl-1H-indol-7-yl)methyl)-2-allyl-N-benzyl-6-(4--
hydroxy-benzyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6-
H)-carboxamide
[0300] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.360 (s, 1H),
.delta. 8.39 (d, J=8.1 Hz, 1H), .delta. 7.50 (d, J=8.4 Hz, 2H),
.delta. 7.31.about.7.16 (m, 8H), .delta. 6.96.about.6.86 (m, 3H),
.delta. 6.74.about.6.61 (m, 3H), .delta. 5.58.about.5.51 (m, 2H),
.delta. 5.34 (t, J=5.7 Hz, 1H), .delta. 5.16.about.4.99 (m, 3H),
.delta. 4.82 (d, J=16.2 Hz, 1H), .delta. 4.42.about.4.22 (m, 2H),
.delta. 3.47.about.3.26 (m, 7H), .delta. 3.07.about.3.02 (m, J=4.2,
J=12.0 Hz, 1H), .delta. 2.58 (s, 3H), .delta. 2.36 (s, 3H)
(6S,9aS)-8-((3-acetyl-1H-indol-7-yl)methyl)-2-allyl-N-benzyl-6-(4-hydroxy--
benzyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carbo-
xamide
[0301] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.42.about.3.96
(d, J=7.9 Hz, 1H), .delta. 8.01 (s, 1H), .delta. 7.91.about.7.90
(d, J=3.0 Hz, 1H), .delta. 7.41.about.7.18 (m, 4H), .delta. 7.07
(d, J=7.2 Hz, 1H), .delta. 6.91 (d, J=8.4 Hz, 2H), .delta. 6.75 (t,
J=6.1 Hz, 1H), .delta. 6.60 (d, J=8.4 Hz, 2H), .delta.
5.65.about.5.56 (m, 1H), .delta. 5.42 (t, J=7.2 Hz, 1H), .delta.
5.29.about.5.15 (m, 3H), .delta. 4.97 (d, J=17.4 Hz, 1H), .delta.
4.48.about.4.32 (m, 3H), .delta. 3.43.about.3.22 (m, 7H), .delta.
2.88 (s, 3H)
(6S,9aS)-2-allyl-8-(2-(allyloxy)benzyl)-N-benzyl-6-(4-hydroxy-benzyl)-4,7--
dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0302] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.39.about.7.19
(m, 7H), .delta. 6.98.about.6.93 (m, 2H), .delta. 6.86 (d, J=8.1
Hz, 2H), .delta. 6.72 (t, J=6.0 Hz, 1H), .delta. 6.62 (d, J=8.4 Hz,
2H), .delta. 6.06.about.5.96 (m, 1H), .delta. 5.65.about.5.56 (m,
1H), .delta. 5.48 (dd, J=4.2 Hz, J=10.5 Hz, 1H), .delta.
5.40.about.5.23 (m, 3H), .delta. 5.13 (d, J=10.2 Hz, 1H), .delta.
5.00 (d, J=17.1 Hz, 1H), .delta. 4.88 (d, J=14.7 Hz, 1H), .delta.
4.59.about.4.53 (m, 3H), .delta. 4.46.about.4.31 (m, 2H), .delta.
3.53.about.3.27 (m, 7H)
(6S,9aS)
2-allyl-8-(2-allyloxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexa-
hydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0303] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 1.87-1.91 (m,
4H), 3.04-3.14 (m, 5H), 3.27-3.48 (m, 7H), 4.32 (dd, J=6 Hz, J=14.9
Hz, 1H), 4.39 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.59 (d, J=15.2 Hz, 1H),
4.90-4.97 (m, 2H), 5.07 (d, J=10.3 Hz, 1H), 5.38 (t, J=5.6 Hz, 1H),
5.48-5.58 (m, 2H), 6.65-6.69 (m, 3H), 6.65 (d, J=9 Hz, 3H),
6.94-6.98 (m, 2H), 7.01 (d, J=9 Hz, 3H), 7.23-7.38 (m, 6H)
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(3-phenyl-allyl)-octahyd-
ro-pyrido[3,4-c]pyridazine-1-carboxylic acid benzylamide
[0304] .sup.1H NMR (300 MHz, D.sub.2O): .delta. 7.39.about.7.24 (m,
10H), 6.98 (d, J=8.5 Hz, 2H), 6.91 (s, OH), 6.72 (t, J=6.0 Hz, NH),
6.61 (d, J=8.3 Hz, 2H), 6.52 (d, J=15.9 Hz, 1H), 6.18.about.6.08
(m, 1H), 5.71.about.5.58 (m, 1H), 5.47 (dd, J=10.7 Hz 4.0 Hz, 1H),
J=5.6 Hz, 1H), 5.17 (d, J=8.8 Hz, 1H), 5.12 (d, J=15.9 Hz, 1H),
4.48.about.4.31 (m, 3H), 4.03 (dd, J=15.0 Hz 7.5 Hz, 1H),
3.59.about.3.28 (m, 9H)
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-((6-nitrobenzo[d][1,3]dio-
xol-5-yl)methyl)-4,7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(-
6H)-carboxamide
[0305] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.50 (s, 1H),
.delta. 7.34.about.7.18 (m, 5H), .delta. 7.96 (d, J=8.4 Hz, 2H),
.delta. 6.70.about.6.54 (m, 3H), .delta. 6.06 (d, J=13.2 Hz, 2H),
.delta. 5.66.about.5.55 (m, 1H), .delta. 5.3.about.15.12 (m, 5H),
.delta. 4.60 (d, J=16.5 Hz, 1H), .delta. 4.40.about.4.24 (m, 2H),
.delta. 3.59.about.3.18 (m, 8H)
(6S,9aS)
2-allyl-8-(2,2-difluoro-benzo[1,3]dioxol-4-ylmethyl)-6-(4-hydroxy-
-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0306] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.28-3.35 (m,
5H), 3.47-3.62 (m, 3H), 4.32 (dd, J=6.0 Hz, 1H), 4.41 (dd, J=6.0
Hz, 1H), 4.53 (d, J=15.0 Hz, 1H), 4.86 (d, J=15.0 Hz, 1H), 5.10 (d,
J=17.4 Hz, 1H), 5.19 (d, J=10 Hz, 1H), 5.30 (t, J=5.6 Hz, 1H), 5.45
(dd, J=4.0 Hz, J=10.0 Hz, 1H), 5.59-5.65 (m, 1H), 6.65 (d, J=8.4
Hz, 2H), 6.71 (t, J=5.8 Hz, NH), 6.97-7.10 (m, 4H), 7.24-7.40 (m,
6H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(1H-indol-7-ylmethyl)-4,7-dioxo-he-
xahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
(pyridin-2-ylmethyl)-amide
[0307] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.26-3.51 (m,
8H), 4.29 (d, J=14 Hz, 1H), 4.48 (dd, J=5.4 Hz, J=16 Hz, 1H), 4.51
(dd, J=5.4 Hz, J=16 Hz, 1H), 4.97 (d, J=17 Hz, 1H), 5.13 (d, J=10
Hz, 1H), 5.24-5.37 (m, 3H), 5.70-5.72 (m, 1H), 6.54 (d, J=8.4 Hz,
2H), 6.93 (d, J=8.4 Hz, 1H), 6.97-7.01 (m, 1H), 7.20-7.28 (m, 4H),
7.4 (t, J=5.5 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.67-7.72 (m, 1H),
8.54 (d, J=4.8 Hz, 1H), 9.96 (s, NH)
(6S,9aS)
2-allyl-8-(2-difluoromethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dio-
xo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0308] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.10-7.39 (m,
10H), 6.95 (d, J=8.4 Hz, 2H), 6.71 (t, J=5.7 Hz, 1H), 6.63 (d,
J=8.4 Hz), 5.56-5.66 (m, 1H), 5.43 (dd, J=3.9 Hz, 10.5 Hz, 1H),
5.30 t, J=5.4 Hz, 1H), 5.08-5.16 (m, 2H), 4.80 (d, J=15 Hz, 1H),
4.59 (d, J=15 Hz, 1H), 4.29-4.46 (m, 2H), 3.25-3.54 (m, 8H)
(6S,9aS)-2-allyl-N-benzyl-8-((3-(cyclopropanecarbonyl)-1-tosyl-1H-indol-7--
yl)methyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2-
,4]triazine-1(6H)-carboxamide
[0309] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.56 (s, 1H),
.delta. 8.34 (d, J=7.5 Hz, 1H), .delta. 7.56 (d, J=8.4 Hz, 2H),
.delta. 7.36.about.7.20 (m, 7H), .delta. 7.00 (d, J=8.4 Hz, 1H),
.delta. 6.92 (d, J=7.5 Hz, 1H), .delta. 6.72 (t, J=6.0 Hz, 1H),
.delta. 6.65 (d, J=8.1 Hz, 2H), .delta. 6.52 (s, 1H), .delta.
5.83.about.5.71 (m, 1H), .delta. 5.59 (dd, J=6.0 Hz, J=11.1 Hz,
1H), .delta. 5.39 (t, J=5.7 Hz, 1H), .delta. 5.20.about.4.87 (m,
4H), .delta. 4.67.about.4.27 (m, 2H), .delta. 3.57.about.3.29 (m,
7H), .delta. 3.08 (dd, J=4.2 Hz, J=12.0 Hz, 1H), .delta.
2.54.about.2.48 (m, 1H), .delta. 1.27.about.1.24 (m, 2H), .delta.
1.07.about.1.03 (m, 2H)
(6S,9aS)
2-allyl-8-[1-(4-chloro-benzenesulfonyl)-1H-indol-7-ylmethyl]-6-(4-
-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carb-
oxylic acid benzylamide
[0310] .sup.1H NMR (CDCl.sub.3): .delta. 7.614.about.7.601 (d,
J=12.0 Hz, 1H), 7.526.about.7.498 (d, J=8.4 Hz, 2H),
7.434.about.7.410 (d, J=7.2 Hz, 1H), 7.361.about.7.218 (m, 8H),
6.954.about.6.929 (d, J=7.5 Hz, 1H), 6.718.about.6.670 (m, 3H),
5.682.about.5.506 (m, 2H), 5.541.about.5.342 (m, 2H),
5.155.about.5.091 (dd, J=10.5 Hz, J=10.5 Hz, 1H), 5.034.about.5.924
(dd, J=16.5 Hz, J=16.5 Hz, 1H), 4.455.about.4.462 (dt, J=6.0 Hz,
J=15.0 Hz, 2H), 3.515.about.3.318 (m, 6H), 3.130.about.3.077 (dd,
J=4.2 Hz, J=12.0 Hz, 1H)
(6S,9aS)-2-allyl-N-benzyl-8-((3-(cyclopropanecarbonyl)-1H-indol-7-yl)methy-
l)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triaz-
ine-1(6H)-carboxamide
[0311] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.42 (d, J=7.8 Hz,
1H), .delta. 8.04 (d, J=3.0 Hz, 2H), .delta. 7.40.about.7.17 (m,
5H), .delta. 7.07 (d, J=6.6 Hz, 1H), .delta. 6.92 (d, J=8.4 Hz,
1H), .delta. 6.77 (t, J=6.0 Hz, 1H), .delta. 6.59 (d, J=8.4 Hz,
2H), .delta. 5.64.about.5.55 (m, 1H), .delta. 5.45 (t, J=6.0 Hz,
1H), .delta. 5.35.about.5.26 (m, 2H), .delta. 5.16 (d, J=10.2 Hz,
1H), .delta. 4.95 (d, 17.1 Hz, 1H), .delta. 4.46.about.4.29 (m,
3H), .delta. 3.43.about.3.20 (m, 8H), .delta. 2.51.about.2.44 (m,
1H), .delta. 1.26.about.1.20 (m, 2H), .delta. 0.97.about.0.92 (m,
2H)
[0312] (6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-prop-2-ynyl-hexahydro-pyrazino[2-
,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
[0313] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.23.about.7.38
(m, 5H), 6.91 (d, J=8.4 Hz, 2H), 6.75 (s, 1H), 6.70 (t, J=6.0 Hz,
1H), 6.57 (d, J=8.4 Hz, 2H), 5.59.about.5.73 (m, 1H), 5.42 (dd,
J=4.2 Hz, 10.8 Hz, 1H), 5.17.about.5.28 (m, 3H), 4.29.about.4.56
(m, 3H), 3.99.about.4.05 (m, 1H), 3.37.about.3.68 (m, 8H
3-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-benzoic acid methyl ester
[0314] .sup.1H NMR (CDCl.sub.3): .delta. 7.993.about.7.957 (m, 1H),
7.906 (s, 1H), 7.446.about.7.245 (m, 7H), 6.991.about.6.963 (d,
J=8.4 Hz, 2H), 6.702.about.6.662 (t, J=6.0 Hz, 1H),
6.629.about.6.601 (d, J=8.4 Hz, 2H), 5.666.about.5.532 (dt, J=6.3
Hz, J=8.1 Hz, 1H), 5.467.about.5.417 (dd, J=4.2 Hz, J=10.8 Hz, 1H),
5.348.about.5.310 (t, J=5.7 Hz, 1H), 5.145.about.5.110 (d, J=10.5
Hz, 1H), 5.014.about.4.957 (d, J=17.1 Hz, 1H), 4.919.about.4.870
(d, J=14.7 Hz, 1H), 4.483.about.4.454 (d, J=8.7 Hz, 1H),
4.483.about.4.282 (dd, J=5.7 Hz, J=14.7 Hz, 2H), 3.911 (s, 3H),
3.454.about.3.212 (m, 8H), 3-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-benzoic acid
[0315] .sup.1H NMR (CDCl.sub.3): .delta. 7.976.about.7.954 (d,
J=6.6 Hz 1H), 7.665 (s, 1H), 7.426.about.7.211 (m, 6H),
7.006.about.6.981 (d, =7.5 Hz, 2H), 6.847.about.6.739 (dd, J=8.4
Hz, J=13.2 Hz, 2H), 6.574.about.6.535 (t, J=5.7 Hz, 1H),
5.616.about.5.504 (dt, J=4.2 Hz, J=6.3 Hz, 1H), 5.209.about.4.859
(m, 5H), 4.235.about.3.939 (m, 4H), 3.539.about.3.094 (m, 4H)
(6S,9aS)
2-allyl-8-benzo[b]thiophen-3-ylmethyl-6-(4-hydroxy-benzyl)-4,7-di-
oxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0316] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 3.18.about.3.3 (m,
5H), 3.34.about.3.41 (m, 3H), 4.27 (dd, J=6 Hz, J=15 Hz, 1H), 4.36
(dd, J=6 Hz, J=15 Hz, 1H), 4.47 (d, J=14.7 Hz, 1H), 4.70 (d, J=17.1
Hz, 1H), 4.99 (d, J=10.5 Hz, 1H), 5.26.about.5.34 (m, 2H),
5.37.about.5.54 (m, 2H), 6.56 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz,
2H), 7.19.about.7.42 (m, 8H), 7.82.about.7.89 (m, 2H)
2-{3-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-benzoylamino}-pentanedioic
acid
[0317] .sup.1H NMR (DMSO-D6): .delta. 8.180.about.8.108 (m, 1H),
7.812.about.7.227 (m, 10H), 6.881.about.6.853 (d, J=8.4 Hz, 2H),
6.599.about.6.572 (d, J=8.4 Hz, 2H), 5.873.about.5.737 (m, 1H),
5.352.about.5.288 (m, 1H), 5.105.about.5.036 (m, 3H),
4.852.about.4.803 (d, J=13.2 Hz, 1H), 4.384.about.4.142 (m, 4H),
3.689.about.3.477 (m, 4H), 3.283.about.3.028 (m, 5H),
2.411.about.1.860 (m, 4H),
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-7-[2-(4-methoxy-phenyl)-pyridin-3-yl-
methyl]-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic
acid benzylamide
[0318] 1H NMR (300 MHz, CDCl.sub.3): .delta. 8.59 (dd, J=4.8 Hz 1.5
Hz, 1H), 7.42.about.7.20 (m, 9H), 6.97.about.6.93 (m, 4H), 6.75
(brs, OH), 6.66 (t, J=5.9 Hz, NH), 6.60 (d, J=8.5 Hz, 2H),
5.64.about.5.50 (m, 1H), 5.41 (dd, J=10.6 Hz 3.7 Hz, 1H), 5.24 (t,
J=5.5 Hz, 1H), 5.13 (d, J=9.8 Hz, 1H), 5.01 (d, J=17.1 Hz, 1H),
4.86 (d, J=15.6 Hz, 1H), 4.70 (d, J=15.5 Hz, 1H), 4.43.about.4.25
(m, 2H), 3.83 (s, 3H), 3.46.about.3.18 (m, 7H), 2.92 (dd, J=11.8 Hz
3.9 Hz, 1H)
(6S,9aS)
8-[3-Acetyl-1-(4-chloro-benzenesulfonyl)-1H-indol-7-ylmethyl]-2-a-
llyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazi-
ne-1-carboxylic acid benzylamide
[0319] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.34 (s, 2H)
.delta. 7.60 (d, J=9.7 Hz, 2H) .delta. 7.36.about.7.21 (m, 6H)
.delta. 6.99 (d, J=8.2 Hz, 2H) .delta. 6.93 (d, J=8.3 Hz, 1H)
.delta. 6.73.about.6.65 (m, 1H) .delta. 5.66.about.5.52 (m, 2H)
.delta. 5.37 (t, J=5.6 Hz, 1H) .delta. 5.29 (s, 1H) .delta.
5.24.about.5.04 (m, 3H) .delta. 4.81 (d, J=6.2 Hz, 1H) .delta.
4.45.about.4.26 (dd, J=5.0 Hz, J=5.0 Hz, 2H) .delta.
3.51.about.3.31 (m, 7H) .delta. 3.71.about.3.61 (m, 2H) .delta.
3.13.about.3.07 (dd, J=4.0 Hz, J=3.9 Hz, 1H) .delta. 2.58 (s,
3H)
(6S,9aS)-2-allyl-N-benzyl-6-(4-hydroxy-benzyl)-8-(2-(methylthio)benzyl)-4,-
7-dioxo-hexahydro-2,1-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
[0320] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.38.about.7.23
(m, 6H), .delta. 7.15 (t, J=7.5 Hz, 1H), .delta. 7.08 (d, J=7.5 Hz,
2H), .delta. 7.01 (d, J=8.4 Hz, 2H), .delta. 6.70.about.6.63 (m,
3H), .delta. 6.37 (s, 1H), .delta. 5.63.about.5.49 (m, 1H), .delta.
5.35 (t, J=5.4 Hz, 1H), .delta. 5.10 (d, J=10.2 Hz, 1H), .delta.
4.98.about.4.88 (m, 3H), .delta. 4.65 (d, J=15.0 Hz, 1H), .delta.
4.47.about.4.27 (m, 2H), .delta. 3.47.about.3.28 (m, 8H), .delta.
2.45 (s, 3H)
(6S,9aS)
2-allyl-8-dibenzofuran-4-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo--
hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0321] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.87.about.7.95
(m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.21.about.7.38 (m, 9H), 7.45 (t,
J=7.2 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 6.65 (t, J=6.0 Hz, 1H), 6.54
(d, J=8.4 Hz, 2H), 5.46.about.5.51 (m, 2H), 5.34 (t, J=5.7 Hz, 1H),
5.17 (m, 1H), 4.75.about.4.97 (m, 3H), 4.32.about.4.41 (m, 2H),
3.22.about.3.58 (m, 8H)
(2S,6S,9aS)
2-allyl-7-(2,3-dimethoxy-benzyl)-5-(4-hydroxy-benzyl)-4,6-dioxo-octahydro-
-[1,7]naphthyridine-1-carboxylic acid benzylamide
[0322] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.38.about.7.29
(m, 3H), 7.19 (d, J=7.1 Hz, 2H), 6.98 (dd, J=8.1 Hz 8.1 Hz, 1H),
6.88.about.6.77 (m, 4H), 6.51 (d, J=8.4 Hz, 2H), 5.68.about.5.55
(m, 1H), 5.26 (t, J=5.0 Hz, 1H), 5.05 (d, J=9.7 Hz, 1H), 5.00 (d,
J=18.6 Hz, 1H), 4.87 (d, J=14.5 Hz, 1H), 4.58.about.4.25 (m, 6H),
3.84 (s, 3H), 3.69 (s, 3H), 3.47.about.3.34 (m, 2H),
3.26.about.3.20 (m, 2H), 2.58.about.2.41 (m, 2H), 2.23 (t, J=7.4
Hz, 2H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(2-methanesulfonyl-benzyl)-4,7-dio-
xo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0323] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.04 (d, J=7.8 Hz,
1H), .delta. 7.62 (t, J=6.6 Hz, 1H), .delta. 7.46 (d, J=7.5 Hz,
1H), .delta. 7.38.about.7.17 (In, 3H), .delta. 6.97.about.6.87 (m,
3H), .delta. 6.75.about.6.66 (m, 3H), .delta. 5.71.about.5.52 (m,
2H), .delta. 5.36.about.5.29 (m, 2H), .delta. 5.21.about.5.12 (m,
2H), .delta. 4.85 (d, J=16.2 Hz, 1H), .delta. 4.46.about.4.29 (m,
2H), .delta. 3.70.about.3.32 (m, 8H), .delta. 3.14 (s, 3H)
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-7-[2-(4-hydroxy-phenyl)-pyridin-3-yl-
methyl]-4,6-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic
acid benzylamide
[0324] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.54.about.8.45
(m, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.34.about.7.18 (m, 8H), 6.89 (d,
J=8.2 Hz, 2H), 6.66.about.6.63 (m, 3H), 6.59 (d, J=8.3 Hz, 2H),
5.60.about.5.47 (m, 1H), 5.16.about.5.07 (m, 4H), 4.96 (d, J=17.3
Hz, 1H), 4.45 (d, J=15.7 Hz, 1H), 4.40.about.4.21 (m, 2H),
3.46.about.3.12 (m, 7H), 2.87.about.2.83 (m, 1H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(1-methyl-1H-indol-3-ylmethyl)-4,7-
-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carb oxylic acid
benzylamide
[0325] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.19 (d, J=16.8
Hz, 1H), 3.27.about.3.40 (m, 7H), 3.75 (s, 3H), 4.27 (dd, J=6 Hz,
J=15 Hz, 1H), 4.40.about.4.46 (m, 2H), 4.75 (d, J=17 Hz, 1H), 5.02
(d, J=10.2 Hz, 1H), 5.13 (d, J=14.4 Hz, 1H), 5.26 (t, J=5.7 Hz,
1H), 5.38 (dd, J=4.5 Hz, J=9.9 Hz, 1H), 5.48.about.5.61 (m, 1H),
5.97 (s, OH), 6.57 (d, J=8.4 Hz, 2H), 6.67 (d, J=6 Hz, NH), 6.97
(d, J=8.4 Hz, 3H), 7.13 (t, J==7.5 Hz, 1H), 7.29.about.7.39 (m,
6H), 7.65 (d, J=8.4 Hz, 1H)
(6S,9aS)
2-allyl-8-[2-(4-chloro-phenylsulfanyl)-benzyl]-6-(4-hydroxy-benzy-
l)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0326] .sup.1H NMR (CDCl.sub.3): .delta. 7.391.about.7.073 (m,
16H), 6.993.about.6.965 (d, J=8.4 Hz, 2H), 7.906 (s, 1H),
7.446.about.7.245 (m, 7H), 6.991.about.6.963 (d, J=8.4 Hz, 2H),
6.719.about.6.679 (t, J=-6.0 Hz, 1H), 6.652.about.6.624 (d, J=8.4
Hz, 2H), 5.660.about.5.526 (dt, J=6.3 Hz, J=16.8 Hz, 1H),
5.500.about.5.452 (dd, J=3.9 Hz, J=10.5 Hz, 1H), 5.338.about.5.303
(t, J=5.1 Hz, 1H), 5.148.about.5.114 (d, J=10.1 Hz, 1H),
5.043.about.4.986 (d, J=17.1 Hz, 1H), 4.835.about.4.824 (d, J=0.3
Hz, 1H), 4.477.about.4.283 (dd, J=3.0 Hz, J=5.7 Hz, 2H),
3.485.about.3.125 (m, 8H),
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-[1-(toluene-4-sulfonyl)--
1H-indol-3-ylmethyl]-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0327] .sup.1H NMR (CDCl.sub.3): .delta. 7.969.about.7.942 (d, J=83
Hz, 1H), 7.782.about.7.754 (d, J=8.4 Hz, 2H), 7.626.about.7.600 (d,
J=7.8 Hz, 1H), 7.483 (s, 1H), 7.399.about.7.180 (m, 11H),
6.978.about.6.950 (d, J=8.4 Hz, 2H), 6.691.about.6.650 (t, J=6.0
Hz, 1H), 6.631.about.6.603 (d, J=8.4 Hz, 2H), 5.663.about.5.466 (m,
1H), 5.319.about.5.038 (m, 4H), 4.882.about.4.825 (d, J=17.1 Hz,
1H), 4.481.about.4.378 (m, 3H), 3.460.about.3.247 (m, 8H), 2.284
(s, 3H)
(6S,9aS)
2-allyl-8-[2-(4-chloro-benzenesulfonyl)-benzyl]-6-(4-hydroxy-benz-
yl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0328] .sup.1H NMR (CDCl.sub.3): .delta. 8.156.about.8.126 (dd,
J=1.2 Hz, J=7.8 Hz, 1H), 7.780.about.7.751 (d, J=6.9 Hz, 2H),
7.622.about.7.223 (m, 10H), 7.137.about.7.112 (d, J=7.5 Hz, 1H),
6.994.about.6.966 (d, J=8.4 Hz, 2H), 6.731.about.6.691 (t, J=6.0
Hz, 1H), 6.669.about.6.641 (d, J=8.4 Hz, 2H), 5.689.about.5.555
(dt, J=6.6 Hz, J=10.5 Hz, 1H), 5.511.about.5.462 (dd, J=3.9 Hz,
J=10.8 Hz, 1H), 5.362.about.5.327 (t, J=5.3 Hz, 1H),
5.196.about.5.161 (d, J=10.5 Hz, 1H), 5.134.about.5.107 (d, J=8.1
Hz, 1H), 5.077.about.5.054 (d, J=6.9 Hz, 1H), 4.841.about.4.788 (d,
J=15.9 Hz, 1H), 4.461.about.4.273 (dd, J=6.3 Hz, J=15.0 Hz, 2H),
3.519.about.3.322 (m, 8H), 4.461.about.4.273 (dd, J=3.6 Hz, J=11.7
Hz, 1H)
Toluene-4-sulfonic acid 2-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-6-methoxy-phenyl ester
[0329] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.86 (d, J=8.7
Hz), 7.52 (d, J=7.2 Hz, 2H), 7.19-7.39 (m, 6H), 7.00 (d, J=8.4 Hz,
2H), 6.71-6.84 (m, 3H), 6.64 (d, J=8.4 Hz, 2H), 5.50-5.67 (m, 2H),
5.36 (t, J=5.4 Hz, 1H), 5.30 (s, 1H), 5.07-5.17 (m, 2H), 4.76-4.93
(m, 2H), 4.30-4.47 (m, 2H), 3.27-3.61 (m, 11H)
(6S,9aS)
2-allyl-8-(3-allyloxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexa-
hydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0330] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.23 (d, J=17 Hz,
1H), 3.30-3.37 (m, 4H), 3.41-3.49 (m, 3H), 4.27 (dd, J=6 Hz, J=15
Hz, 1H), 4.38 (dd, J=6 Hz, J=1 Hz, 1H), 4.49-4.56 (m, 3H), 4.78 (d,
J=15 Hz, 1H), 4.95 (d, J=17 Hz, 1H), 5.07 (d, J=10 Hz, 1H),
5.19-5.27 (m, 2H), 5.30 (dd, J=1.5 Hz, J=17.4 Hz, 1H), 5.38 (dd,
J=4.2 Hz, J=10.8 Hz, 1H), 5.51-5.67 (m, 1H), 5.92-6.02 (m, 1H),
6.35 (s, OH), 6.57 (d, J=8.4 Hz, 2H), 6.64 (t, J=6.3 Hz, NH), 6.81
(d, J=8.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 3H), 7.16-7.20 (m, 3H),
7.27-7.36 (m, 4H)
(6S,9aS)
2-allyl-8-(3-tert-butyl-2-methoxy-benzyl)-6-(4-hydroxy-benzyl)-4,-
7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0331] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 1.345 (s, 9H),
3.08 (dd, J=3.9 Hz, J=12 Hz, 1H), 3.22 (d, J=17.1 Hz, 1H),
3.32-3.43 (m, 6H), 3.72 (s, 3H), 4.24 (dd, J=6 Hz, J=15 Hz, 1H),
4.37 (dd, J=6 Hz, J=15 Hz, 1H), 4.47 (d, J=15 Hz, 1H), 4.87 (d,
J=18 Hz, 1H), 5.04-5.11 (m, 2H), 5.34 (t, J=5.7 Hz, 1H), 5.49-5.58
(m, 2H), 6.61-6.67 (m, 3H), 6.85 (s, OH), 6.90-6.93 (m, 1H),
6.98-7.02 (m, 3H), 7.19-7.23 (m, 4H), 7.30-7.36 (m, 2H)
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(4-pyrrolidin-1-yl-3,4,5-
,6-tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl)-octahydro-pyrido[3,4-c]pyr-
idazine-1-carboxylic acid benzylamide
[0332] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.22 (dd, J=4.8
Hz 1.5 Hz, 1H), 7.38.about.7.21 (m, 6H), 7.02 (d, J=8.4 Hz, 2H),
6.93 (dd, J=7.6 Hz 4.9 Hz, 1H), 6.77.about.6.63 (m, 3H),
5.68.about.5.54 (m, 1H), 5.42 (dd, J=11.4 Hz 3.9 Hz, 1H), 5.36 (t,
J=5.2 Hz, 1H), 5.15 (d, J=10.3 Hz, 1H), 5.07 (d, J=17.0 Hz, 1H),
4.78 (d, J=15.4 Hz, 1H), 4.48 (d, J=15.4 Hz, 1H), 4.43.about.4.26
(m, 2H), 3.50.about.3.24 (m, 9H), 3.02.about.2.68 (m, 7H),
2.36.about.1.70 (m, 8H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(3-methoxy-2-vinyloxy-benzyl)-4,7--
dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0333] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.23-7.39 (m, 5H),
6.97-7.07 (m, 4H), 6.61-6.88 (m, 7H), 6.00-6.09 (m, 1H), 5.55-5.60
(m, 1H), 5.48 (dd, J=4.2 Hz, 10.8 Hz, 1H), 4.92-5.33 (m, 7H),
4.29-4.59 (m, 6H), 3.85 (s, 3H), 3.23-3.47 (m, 10H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-phenoxy-benzyl)-hexah-
ydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0334] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.18-3.44 (m,
8H), 4.29 (dd, J=5.6 Hz, J=15.1 Hz, 1H), 4.38-4.45 (m, 2H), 4.72
(d, J=14.8 Hz, 1H), 4.98 (d, J=17 Hz, 1H), 5.03 (d, J=10.4 Hz, 1H),
5.26 (t, J=5.8 Hz, 1H), 5.41 (dd, J=3.9 Hz, J=10.7 Hz, 1H),
5.55-5.64 (m, 1H), 6.32 (s, OH), 6.57 (d, J=8.4 Hz, 2H), 6.60 (t,
J=6 Hz, NH), 6.87-6.99 (m, 7H), 7.07 (t, J=7.4 Hz, 1H), 7.21 (s,
1H), 7.27-7.37 (m, 7H)
(6S,9aS)
2-allyl-8-[2-(benzyl-methyl-amino)-benzyl]-6-(4-hydroxy-benzyl)-4-
,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0335] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.35.about.6.00
(m, 18H) .delta. 6.70.about.6.63 (m, 3H) .delta. 5.59.about.5.40
(m, 2H) .delta. 5.38 (t, J=5.7 Hz, 1H) .delta. 5.02 (d, J=10.3 Hz,
1H) .delta. 4.98.about.4.81 (dd, J=5.7 Hz, J=5.5 Hz, 2H) .delta.
4.44.about.4.28 (dd, J=4.9 Hz, J=4.9 Hz, 1H) .delta. 3.97 (s, 2H)
.delta. 3.46.about.3.25 (m, 7H) .delta. 3.19.about.3.14 (dd, J=4.1
Hz, J=4.2 Hz, 1H) .delta. 2.54 (s, 3H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(3-methyl-but-2-enoyl)-1-(tolue-
ne-4-sulfonyl)-1H-indol-7-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,-
2,4]triazine-1-carboxylic acid benzylamide
[0336] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.41 (d, J=9.3 Hz,
2H), .delta. 7.53 (d, J=8.4 Hz, 2H), .delta. 7.35.about.7.20 (m,
8H), .delta. 7.01 (d, J=8.4 Hz, 2H), .delta. 6.93 (d, J=7.8 Hz,
1H), .delta. 6.75 (t, J=6.0 Hz, 1H), .delta. 6.66 (d, J=8.4 Hz,
2H), .delta. 5.69.about.5.56 (m, 2H), .delta. 5.40 (t, J=5.7 Hz,
1H), .delta. 5.21.about.4.90 (m, 4H), .delta. 4.46.about.4.16 (m,
2H), .delta. 3.51.about.3.30 (m, 6H), .delta. 3.10 (dd, J=3.9 Hz,
J=11.7 Hz, 1H), .delta. 2.35 (s, 3H), 2.27 (s, 3H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(3-methyl-but-2-enoyl)-1H-indol-
-7-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxyl-
ic acid benzylamide
[0337] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.49 (d, J=7.8 Hz,
1H), .delta. 7.90 (d, J=3.0 Hz, 1H), .delta. 7.40.about.7.17 (m,
6H), .delta. 7.06 (d, J=4.5 Hz, 1H), .delta. 6.90 (d, J=8.4 Hz,
2H), .delta. 6.81 (t, J=6.0 Hz, 1H), .delta. 6.63.about.6.55 (m,
3H), .delta. 5.65.about.5.54 (m, 1H), .delta. 5.30.about.5.14 (m,
3H), .delta. 3.44.about.3.20 (m, 8H), .delta. 2.24 (s, 3H), .delta.
1.90 (s, 3H)
(6S,9aS)-2-allyl-8-[3-(3-ethoxy-butyryl)-1,1-indol-7-ylmethyl]-6-(4-hydrox-
y-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0338] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.40 (d, J=8.1 Hz,
1H), .delta. 7.85 (dd, J=3.0 Hz, J=21.9 Hz, 1H), .delta.
7.37.about.7.15 (m, 5H), .delta. 7.04 (d, f=7.2 Hz, 1H), .delta.
6.82 (t, J=8.1 Hz, 2H), .delta. 6.71.about.6.68 (m, 1H), .delta.
6.51.about.6.47 (m, 2H), .delta. 5.66.about.5.47 (m, 1H), .delta.
4.57.about.4.30 (m, 3H), .delta. 3.61.about.3.11 (m, 8H), .delta.
2.84.about.2.71 (m, 1H), .delta. 1.57 (s, 3H), .delta.
1.14.about.1.09 (m, 3H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[5-methoxy-1-(toluene-4-sulfonyl)--
1H-indol-3-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1--
carboxylic acid benzylamide
[0339] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 2.28 (s, 3H),
3.24-3.38 (m, 8H), 3.80 (s, 3H), 4.38-4.47 (m, 3H), 4.88 (d, J=17.2
Hz, 1H), 4.94 (d, J=14.9 Hz, 1H), 5.10 (d, J=11 Hz, 1H), 5.25-5.32
(m, 1H), 6.01 (s, OH), 6.59 (d, J=8.5 Hz, 2H), 6.66 (t, J=6.1 Hz,
NH), 6.92-6.96 (m, 3H), 7.11 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.2 Hz,
2H), 7.32-7.42 (m, 6H), 7.72 (d, J=8.4 Hz, 2H), 7.82 (d, J=9 Hz,
1H)
Dodecane-1-sulfonic acid 2-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-phenyl ester
[0340] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.84 (t, J=6.9
Hz, 3H), 1.23 (brs, 15H), 1.39-1.46 (m, 2H), 1.93 (q, T=7.7 Hz,
2H), 3.12 (dd, J=4.1 Hz, J=11.8 Hz, 1H), 3.21 (d, J=17.1 Hz, 1H),
3.26-3.45 (m, 9H), 4.25-4.30 (m, 2H), 4.38 (dd, J=6 Hz, J=14.9 Hz,
1H), 4.77 (d, J=7.2 Hz, 1H), 5.01 (d, J=10.4 Hz, 1H), 5.22-5.27 (m,
2H), 6.58 (d, J=8.3 Hz, 2H), 6.66 (t, J=6 Hz, NH), 6.93 (d, J=8.3
Hz, 2H), 7.19-7.38 (m, 9H)
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(2-piperazin-1-yl-pyridi-
n-3-ylmethyl)-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid
benzylamide
[0341] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.11.about.8.71
(brs, 1H), 7.29.about.6.87 (m, 9H), 6.89 (d, J=7.6 Hz, 2H),
6.67.about.6.61 (m, 3H), 5.54.about.5.44 (brs, 2H), 5.23.about.5.20
(m, 1H), 5.17.about.5.13 (m, 1H), 5.03 (d, J=10.1 Hz, 1H), 4.86 (d,
J=16.5 Hz, 1H), 4.71 (d, J=14.1 Hz, 1H), 4.55 (d, J=14.4 Hz, 1H),
4.32.about.4.16 (m, 2H), 3.50.about.2.98 (m, 16H)
(6S,9aS)
2-allyl-8-(3,5-di-tert-butyl-2-methoxy-benzyl)-6-(4-hydroxy-benzy-
l)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0342] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.38.about.7.31
(q, J=6.1 Hz, 3H) .delta. 7.28.about.7.22 (m, 4H) .delta.
7.04.about.7.00 (m, 3H) .delta. 6.89 (s, 1H) .delta. 6.67 (t, J=6.2
Hz, 1H) .delta. 6.62 (d, J=9.2 Hz, 2H) .delta. 5.71.about.5.66 (dd,
J=4.2 Hz, J=4.1 Hz, 1H) .delta. 5.58.about.5.47 (m, 1H) .delta.
5.29 (d, J=14.2 Hz, 1H) .delta. 5.05 (d, J=10.3 Hz, 1H) .delta.
4.83 (d, J=17.1 Hz, 1H) .delta. 3.73 (s, 3H) .delta. 3.39 (d, J=4.5
Hz, 2H) .delta. 3.33 (d, J=9.6 Hz, 2H) .delta. 3.25.about.3.11 (m,
2H) .delta. 1.37 (s, 9H) .delta. 1.26 (s, 9H)
(6S,9aS)
2-allyl-8-[3-chloro-1-(toluene-4-sulfonyl)-1H-indol-7-ylmethyl]-6-
-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-c-
arboxylic acid benzylamide
[0343] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.65 (s, 1H), 7.47
(d, J=8.32 Hz, 2H), 7.43 (d, J=7.63 Hz, 1H), 7.35.about.7.15 (m,
7H), 7.03 (d, J=8.3 Hz, 2H), 6.98 (d, J=7.52 Hz, 1H), 6.68 (m, 3H),
5.60 (m, 2H), 5.37 (m, 2H), 5.10 (m, 2H), 4.95 (d, J=16.3 Hz, 1H),
4.34 (ddd, J=32.9, 14.9, 6.0 Hz, 2H), 3.40 (m, 7H), 3.07 (dd,
J=11.8, 3.97 Hz, 1H), 2.32 (s, 3H)
(6S,9aS)
2-allyl-8-(2-allyloxy-3-tert-butyl-benzyl)-6-(4-hydroxy-benzyl)-4-
,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0344] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.38.about.7.22
(m, 7H) .delta. 7.07.about.6.94 (m, 4H) .delta. 6.75 (s, 1H)
.delta. 6.69 (d, J=6.0 Hz, 1H) .delta. 6.64 (d, J=8.4 Hz, 2H)
.delta. 6.08.about.5.99 (m, 1H) .delta. 5.61.about.5.48 (m, 1H)
.delta. 5.42.about.5.35 (m, 1H) .delta. 5.27 (d, J=9.4 Hz, 1H)
.delta. 5.10.about.4.90 (m, 2H) .delta. 4.53 (d, J=15.1 Hz, 1H)
.delta. 4.46.about.4.33 (m, 2H) 4.29.about.4.23 (m, 2H) .delta.
3.43 (d, J=6.4 Hz, 2H) .delta. 3.38 (d, J=3.3 Hz, 2H) .delta. 3.33
(d, J=15.7 Hz, 2H) .delta. 1.37 (s, 9H)
(6S,9aS)
2-allyl-8-(3-chloro-1H-indol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-
-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0345] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.99 (s, NH), 7.61
(d, J=7.96 Hz, 1H), 7.37.about.7.2 (m, 6H), 7.05 (d, J=7.77 Hz,
1H), 6.97 (d, J=6.92 Hz, 1H), 6.89 (d, J=8.39 Hz, 2H), 6.65 (t,
J=6.14 Hz, NH), 6.54 (d, J=8.4 Hz, 2H), 5.87 (s, 1H), 5.57 (m, 1H),
5.37 (t, J=7.5 Hz, 1H), 5.24 (m, 2H), 5.14 (d, J=10.2 Hz, 1H), 4.95
(d, J=17.0 Hz, 1H), 4.35 (m, 3H), 3.30 (m, 7H)
(6S,9aS)
2-allyl-8-(3,5-di-tert-butyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dio-
xo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0346] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.40.about.7.20
(m, 6H), 7.07 (d, J=1.70 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.68 (t,
J=6.0 Hz, NH), 6.62 (d, J=8.40 Hz, 2H), 6.20 (brs, OH),
5.64.about.5.55 (m, 1H), 5.37 (t, J=6.2 Hz, 1H), 5.15.about.5.02
(m, 2H), 4.85 (d, J=17.2 Hz, 1H), 4.40 (ddd, J=32.2, 14.8, 6.0 Hz,
2H), 4.15 (d, J=14.4 Hz, 1H), 3.50.about.3.20 (m, 8H), 1.30 (s,
18H).
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-methoxy-2-(2-piperidin-1-yl-eth-
oxy)-benzyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxyl-
ic acid benzylamide
[0347] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.22-7.43 (m, 6H),
7.11 (t, J=3.3 Hz, 1H), 6.63-6.97 (m, 8H), 5.59-5.68 (m, 1H),
5.04-5.22 (m, 5H), 4.25-4.40 (m, 6H), 3.88 (s, 3H), 3.25-3.63 (m,
14H), 1.80-1.88 (m, 4H), 1.43-1.64 (m, 2H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(5-methoxy-1H-indol-3-ylmethyl)-4,-
7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0348] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.24 (d, J=17 Hz,
1H), 3.33-3.45 (m, 7H), 3.84 (s, 3H), 4.33 (dd, J=6 Hz, J=14.9 Hz,
1H), 4.87 (dd, J=6 Hz, J=14.9 Hz, 1H), 4.55 (d, J=14.6 Hz, 1H),
4.83 (d, J=17.1 Hz, 1H), 4.95 (d, J=14.6 Hz, 1H), 5.06 (d, J=10.4
Hz, 1H), 5.26-5.31 (m, 2H), 5.52-5.57 (m, 1H), 6.54 (d, J=8.4 Hz,
1H), 6.69 (t, J=5.4 Hz, NH), 6.84 (dd, J=2.4 Hz, J=8.4 Hz, 1H),
6.93 (d, J=8.4 Hz, 2H), 7.01 (d, J=2.3 Hz, 1H), 7.19-7.24 (m, 3H),
7.29-7.38 (m, 3H), 8.24 (s, 1H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(morpholine-4-carbonyl)-benzyl]-
-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0349] .sup.1H NMR (CDCl.sub.3): .delta. 7.426.about.7.226 (m, 9H),
7.135 (s, 1H), 6.946.about.6.918 (d, J=8.4 Hz, 2H),
6.629.about.6.601 (m, 3H), 5.707.about.5.574 (dt, T=6.0 Hz, J=10.2
Hz, 1H), 5.287.about.5.254 (t, J=5.1, 1H), 5.196.about.5.082 (m,
2H), 4.919.about.4.869 (d, J=15.0 Hz, 1H), 4.424.about.4.255 (m,
3H), 3.522.about.3.154 (m, 8H), 1.669 (s, 3H), 1.257 (s, 3H)
(6S,9aS)
2-allyl-8-(3-cyclopentylcarbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,-
7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0350] .sup.1H NMR (CDCl.sub.3): .delta. 7.724.about.7.700 (d,
J=7.2 Hz, 1H), 7.409.about.7.208 (m, 8H), 6.891.about.6.863 (d,
J=8.4 Hz, 2H), 6.367.about.6.554 (m, 3H), 5.700.about.5.566 (dt,
J=6.6 Hz, J=10.5 Hz, 1H), 5.265.about.4.964 (m, 4H),
3.568.about.3.304 (m, 7H), 2.090.about.1.257 (m, 9H)
Octane-1-sulfonic acid 2-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-6-methoxy-phenyl ester
[0351] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.19-7.39 (m, 5H),
6.93-7.00 (m, 3H), 6.62-6.80 (m, 4H), 5.56-5.66 (m, 1H), 5.46 (dd,
J=3.9 Hz, 11.1 Hz, 1H), 5.33 (t, J=5.4 Hz, 1H), 5.04-5.15 (m, 2H),
4.80 (q, J=15.0 Hz, 2H), 4.27-4.47 (m, 2H), 3.87 (s, 3H), 3.23-3.59
(m, 10H), 1.95-2.04 (m, 2H), 1.17-1.69 (m, 16H), 0.83-0.90 (m,
4H)
CWP232017
(6S,9aS)
2-allyl-8-(2-cyclopropylmethoxy-3-methoxy-benzyl)-6-(4-hydroxy-be-
nzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0352] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.21 (dd, J=4.8
Hz, J=10.1 Hz, 2H), 0.50 (dd, J=5.5 Hz, T=12.4 Hz, 2H),
1.14.about.1.27 (m, 1H), 3.30-3.51 (m, 8H), 3.73-3.79 (m, 2H), 3.82
(s, 3H), 4.29 (dd, J=6 Hz, J=14 Hz, 1H), 4.37 (dd, J=6 Hz, J=14 Hz,
1H), 4.56 (d, J=14.6 Hz, 1H), 4.97-5.03 (m, 2H), 5.09 (d, J=10.3
Hz, 1H), 5.30 (t, J=5.4 Hz, 1H), 5.45 (dd, J=4 Hz, J=10.7 Hz, 1H),
5.56-5.63 (m, 1H), 6.61 (d, J=8.3 Hz, 2H), 6.68 (t, J=5.9 Hz, NH),
6.76 (d, J=7.6 Hz, 1H), 6.83 (d, T=7.3 Hz, 1H), 6.96-7.04 (m, 3H),
7.22-7.37 (m, 5H)
(6S,9aS)
2-allyl-8-(2-cyclopentyloxy-3-methoxy-benzyl)-6-(4-hydroxy-benzyl-
)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0353] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 1.65-1.75 (m,
8H), 3.12 (dd, J=4.1 Hz, J=12 Hz, 1H), 3.19 (d, J=17.1 Hz, 1H),
3.30-3.47 (m, 6H), 3.79 (s, 3H), 4.24 (dd, J=5.8 Hz, J=14.9 Hz,
1H), 4.31 (dd, J=5.8 Hz, J=14.9 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H),
4.75-4.83 (m, 2H), 4.93 (d, J=17.4 Hz, 1H), 5.05 (d, J=10.3 Hz,
1H), 5.27 (t, J=5.8 Hz, 1H), 5.42 (dd, J=3.8 Hz, J=10.8 Hz, 1H),
5.51-5.59 (m, 1H), 6.57 (d, J=8.3 Hz, 2H), 6.68 (d, J=7.6 Hz, 1H),
6.78 (d, J=8.3 Hz, 1H), 6.93-7.00 (m, 3H), 7.27-7.34 (m, 5H)
(6S,9aS)
2-allyl-8-[2-(3-fluoro-phenoxy)-3-methoxy-benzyl]-6-(4-hydroxy-be-
nzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0354] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.11 (dd, J=4 Hz,
J=11.7 Hz, 1H), 3.19-3.25 (m, 3H), 3.27-3.38 (m, 4H), 3.69 (s, 3H),
4.25 (dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.35-4.42 (m, 2H), 4.71 (d,
J=14.7 Hz, 1H), 4.96-5.13 (m, 3H), 5.31 (dd, T=4 Hz, J=10.7 Hz,
1H), 5.51-5.60 (m, 1H), 6.38 (dt, J=2.4 Hz, 1H), 6.54-6.66 (m, 5H),
6.84-6.94 (m, 4H), 7.10-7.20 (m, 3H), 7.28-7.35 (m, 3H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[2-(indan-2-yloxy)-3-methoxy-benzy-
l]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0355] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.17.about.7.35
(m, 7H), 7.15.about.7.05 (m, 2H), 7.0 (t, J=7.9 Hz, 1H),
6.90.about.6.80 (m, 3H), 6.75 (d, J=7.5 Hz, 1H), 6.65 (t, J=5.9 Hz,
NH), 6.54 (d, J=8.3 Hz, 2H), 5.57 (m, 1H), 5.32.about.3.25 (m, 2H),
5.16 (t, J=5.6 Hz, 1H), 5.12 (d, J=10.3 Hz, 1H), 5.03 (d, J=17.2
Hz, 1H), 4.49.about.4.25 (m, 4H), 3.81 (s, 3H), 3.44 (s, 1H), 3.35
(d, J=6.0 Hz, 2H), 3.30.about.3.15 (m, 4H), 3.05 (t, J=3.8 Hz, 4H),
2.94 (dd, J=12.0, 4.0 Hz, 1H).
(6S,9aS)
2-allyl-8-(3-cyclohexylcarbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-
-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0356] .sup.1H NMR (CDCl.sub.3): .delta. 7.741.about.7.717 (d,
J=7.2 Hz, 1H), 7.444.about.7.222 (m, 15H), 6.871.about.6.843 (d,
J=8.4 Hz, 2H), 6.646.about.6.572 (m, 3H), 5.692.about.5.602 (m,
2H), 5.234.about.4.895 (m, 4H), 3.406.about.3.273 (m, 3H),
3.3.571.about.3.305 (m, 7H), 2.047.about.1.1.251 (m, 11H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-{3-[(tetrahydro-furan-2--
ylmethyl)-carbamoyl]-benzyl}-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-ca-
rboxylic acid benzylamide
[0357] .sup.1H NMR (CDCl.sub.3): .delta. 7.966.about.7.902 (m, 1H),
7.483.about.7.200 (m, 8H), 6.824.about.6.796 (d, J=8.4 Hz, 1H),
6.667.about.6.611 (t, J=8.4 Hz, 2H), 6.534.about.6.508 (d, J=7.8
Hz, 1H), 5.763.about.5.681 (m, 1H), 5.503.about.5.326 (m, 1H),
5.261.about.5.167 (m, 3H), 4.963.about.4.825 (m, 1H),
4.516.about.4.203 (m, 2H), 3.942.about.3.465 (m, 8H),
2.187.about.1.406 (m, 7 H)
(6S,9aS)
2-allyl-8-(3-amino-benzo[d]isoxazol-7-ylmethyl)-6-(4-hydroxy-benz-
yl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0358] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.23-3.37 (m,
5H), 3.50-3.54 (m, 3H), 3.74 (t, J=11.2 Hz, 1H), 4.29 (s, NH), 4.77
(d, J=15.3 Hz, 2H), 4.93 (d, J=15.3 Hz, 1H), 5.02 (d, J=17.3 Hz,
1H), 5.05 (d, J=10.3 Hz, 1H), 5.21 (t, J=5.4 Hz, 1H), 5.41 (dd,
J=3.9 Hz, J=10.7 Hz, 1H), 5.72-5.77 (m, 1H), 6.62 (d, J=8.3 Hz,
2H), 6.91 (d, J=8.3 Hz, 2H), 7.20-7.25 (m, 4H), 7.30-7.34 (m, 3H),
7.69 (d, J=7.7 Hz, 1H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(2-nitro-benzyl)-4,7-dioxo-hexahyd-
ro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
[0359] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.03 (d, J=8.1 Hz,
1H), .delta. 7.61 (t, J=7.5 Hz, 2H), .delta. 7.45 (t, J=7.8 Hz,
1H), 7.37.about.7.21 (m, 5H), .delta. 7.01 (d, J=7.8 Hz, 1H),
.delta. 6.99 (d, J=8.1 Hz, 2H), .delta. 6.78.about.6.68 (m, 3H),
.delta. 5.65.about.5.50 (m, 2H), .delta. 5.37.about.5.13 (m, 4H),
.delta. 4.74 (d, J=17.1 Hz, 1H), .delta. 4.44.about.4.29 (m, 2H),
.delta. 3.65.about.3.23 (m, 8H)
(6S,9aS)
2-allyl-8-(3-cyano-2-fluoro-benzyl)-6-(4-hydroxy-benzyl)-4,7-diox-
o-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0360] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.59.about.7.48
(m, 3H), .delta. 7.32 (m, 6H), .delta. 6.93 (d, J=8.4 Hz, 2H),
.delta. 6.75 (t, J=6.0 Hz, 1H), .delta. 6.63 (d, J=8.4 Hz, 2H),
.delta. 5.70.about.5.61 (m, 1H), .delta. 5.44 (dd, J=3.9 Hz, J=10.8
Hz, 1H), .delta. 5.29.about.5.11 (m, 3H), .delta. 4.73.about.4.62
(m, 2H), .delta. 4.45.about.4.36 (m, 2H), .delta. 3.69.about.3.30
(m, 8H)
(6S,9aS)
2-allyl-8-(2-amino-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahyd-
ro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
[0361] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.85.about.7.59
(m, 6H), .delta. 7.08 (t, J=5.8 Hz, 1H), .delta. 6.93.about.6.82
(m, 4H), .delta. 6.67.about.6.59 (m, 4H), .delta. 5.63.about.5.50
(m, 1H), .delta. 5.36 (dd, J=4.3 Hz, J=10.5 Hz, 1H), .delta. 5.21
(t, J=5.7 Hz, 1H), .delta. 5.08 (d, J=10.3 Hz, 1H), .delta.
4.92.about.4.86 (m, 2H), .delta. 4.39.about.4.22 (m, 2H), .delta.
4.16.about.4.04 (m, 1H), .delta. 3.41.about.3.18 (m, 8H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-oxo-2-phenyl-4H-chrom-
en-8-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0362] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.14.about.8.10
(m, 1H), .delta. 7.87 (d, J=6.2 Hz, 2H), .delta. 7.53.about.7.47
(m, 3H), .delta. 7.40.about.7.20 (m, 8H), .delta. 6.98 (d, J=8.3
Hz, 2H), .delta. 6.78 (s, 1H), .delta. 6.72.about.6.68 (m, 3H),
.delta. 5.59.about.5.50 (m, 1H), .delta. 5.38 (dd, J=3.8 Hz, J=10.7
Hz, 2H), .delta. 5.13.about.4.97 (m, 4H), .delta. 4.41.about.4.29
(m, 2H), .delta. 3.60.about.3.32 (m, 8H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(4-oxo-4H-chromen-8-ylme-
thyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0363] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.16 (d, J=7.3 Hz,
1H), .delta. 8.03 (d, J=6.0 Hz, 1H), .delta. 7.69 (d, J=7.4 Hz,
1H), .delta. 7.43.about.7.22 (m, 8H), .delta. 5.70.about.5.61 (m,
1H), .delta. 5.20.about.5.10 (m, 3H), .delta. 5.03 (dd, J=4.3 Hz,
J=10.1 Hz, 1H), .delta. 4.90 (d, J=14.6 Hz, 1H), .delta.
4.75.about.4.68 (m, 4H), .delta. 4.37.about.4.30 (m, 3H), .delta.
3.68.about.3.16 (m, 8H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(2-phenyl-pyridin-3-ylme-
thyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0364] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.49 (d, J=3.4 Hz,
1H), .delta. 7.09.about.7.35 (m, 12H), .delta. 6.83 (d, J=8.3 Hz,
1H), .delta. 6.54 (t, J=5.9 Hz, 1H), .delta. 6.49 (d, J=8.4 Hz,
2H), .delta. 6.05 (s, 1H) .delta. 5.36.about.5.54 (m, 1H), .delta.
5.23 (dd, J=10.6 Hz, J=3.9 Hz, 2H), .delta. 5.08 (t, J=5.3 Hz, 1H),
.delta. 5.01 (d, J=10.4 Hz, 1H), .delta. 4.89 (d, J=14.1 Hz, 1H),
.delta. 4.70 (d, J=15.5 Hz, 1H), .delta. 4.55 (d, J=15.5 Hz, 1H),
.delta. 4.28 (dd, J=14.8 Hz, J=6.4 Hz, 1H), .delta. 4.17 (dd,
J=14.8 Hz, J=6.4 Hz, 1H), .delta. 3.05.about.3.33 (m, 6H), .delta.
2.77 (dd, J=11.8 Hz, J=3.9 Hz, 1H).
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(1-pyridin-2-yl-1H-indol-
-7-ylmethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0365] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.54 (m, 1H), 7.87
(td, J=1.8 Hz, 7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.14.about.7.36
(m, 10H), 6.92-6.98 (m, 3H), 6.58-6.69 (m, 5H), 5.39-5.49 (m, 2H),
4.91-5.10 (m, 4H), 4.69 (d, J=16.8 Hz, 1H), 4.22-4.42 (m, 4H),
3.10-3.48 (m, 8H), 2.88 (dd, J=4.2 Hz, 12.0 Hz, 1H)
(6S,9aS)
2-allyl-8-(1,1-dioxo-1H-1l6-benzo[b]thiophen-3-ylmethyl)-6-(4-hyd-
roxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxyl-
ic acid benzylamide
[0366] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.74 (d, J=9.0 Hz,
1H), .delta. 7.65.about.7.52 (m, 3H), .delta. 7.41.about.7.26 (m,
4H), .delta. 6.98 (d, J=9.0 Hz, 2H), .delta. 6.78.about.6.68 (m,
3H), .delta. 6.41 (s, 1H), .delta. 5.66.about.5.60 (m, 1H), .delta.
5.32.about.5.11 (m, 4H), .delta. 4.68 (d, J=6.0 Hz, 2H), .delta.
4.48.about.4.37 (m, 2H), .delta. 3.59.about.3.30 (m, 8H)
(6S,9aS)
2-allyl-8-(6-bromo-pyridin-2-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-d-
ioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0367] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.52 (t, J=9.0 Hz,
1H), .delta. 7.40.about.7.34 (m, 4H), .delta. 7.25 (d, J=6.0 Hz,
1H), .delta. 7.15 (d, J=6.0 Hz, 1H), .delta. 6.99 (d, J=6.0 Hz,
2H), .delta. 6.74 (t, J=6.0 Hz, 1H), .delta. 6.63 (d, J=9.0 Hz,
2H), .delta. 5.71.about.5.55 (m, 2H), .delta. 5.32 (t, J=6.0 Hz,
1H), .delta. 4.58 (d, J=15.0 Hz, 1H), .delta. 4.45.about.4.33 (m,
2H), .delta. 3.88 (t, J=9.0 Hz, 1H), .delta. 3.63.about.3.31 (m,
7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(6-phenyl-pyridin-2-ylme-
thyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0368] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.98 (d, J=6.0 Hz,
1H), .delta. 7.78.about.7.65 (m, 2H), .delta. 7.47.about.7.38 (m,
5H), .delta. 7.33.about.7.16 (m, 2H), .delta. 7.17 (d, J=6.0 Hz,
1H), .delta. 7.00 (d, J=9.0 Hz, 2H), .delta. 6.72 (t, J=6.0 Hz,
1H), .delta. 6.62 (d, J=6.0 Hz, 2H), .delta. 5.64.about.5.58 (m,
2H), .delta. 5.39 (t, J=6.0 Hz, 1H), .delta. 4.45.about.4.37 (m,
2H), .delta. 3.91 (t, J=12.0 Hz, 1H), 3.57.about.3.28 (m, 7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[6-(2-methoxy-phenyl)-pyridin-2-yl-
methyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0369] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.80.about.7.66
(m, 3H), .delta. 7.39.about.7.32 (m, 3H), .delta. 7.30.about.7.24
(m, 2H), .delta. 7.13 (t, J=6.0 Hz, 1H), .delta. 7.06.about.6.97
(m, 4H), .delta. 6.72 (t, J=6.0 Hz, 1H), .delta. 6.62 (d, J=6.0 Hz,
2H), .delta. 5.66.about.5.57 (m, 21.about.1), .delta. 5.38 (t,
J=6.0 Hz, 1H), .delta. 5.09.about.4.91 (m, 3H), .delta. 4.60 (d,
J=15.0 Hz, 1H), .delta. 4.42.about.4.38 (m, 2H), .delta. 3.91 (t,
J=12.0 Hz, 1H), .delta. 3.85 (s, 3H), .delta. 3.50.about.3.26 (m,
7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-methanesulfonyl-phenyl)-pyri-
din-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carbo-
xylic acid benzylamide
[0370] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.18 (d, J=8.4 Hz,
2H), 8.01 (d, J=9.3 Hz, 2H), 7.71-7.83 (m, 2H), 7.24-7.40 (m, 5H),
6.89 (d, J=8.4 Hz, 2H), 6.74 (t, J=6.0 Hz, 1H), 6.49 (d, J=8.4 Hz,
2H), 5.59-5.68 (m, 1H), 5.51 (dd, J=4.2 Hz, 10.8 Hz, 1H), 5.29-5.36
(m, 1H), 5.13 (d, J=10.2 Hz, 1H), 5.02 (d, J=17.1 Hz, 1H), 4.85 (d,
J=15.3 Hz, 1H), 4.66 (d, J=13.5 Hz, 1H), 4.30-4.49 (m, 2H), 3.84
(t, J=11.2 Hz, 1H), 3.31-3.68 (m, 7H), 3.07 (s, 3H)
(6S,9aS)
2-allyl-8-[6-(4-fluoro-phenyl)-pyridin-2-ylmethyl]-6-(4-hydroxy-b-
enzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0371] .sup.1H NMR (CDCl.sub.3, 300 MHz)), .delta. 7.98.about.7.94
(m, 2H), .delta. 7.73 (t, J=6.0 Hz, 1H), .delta. 7.61 (d, J=9.0 Hz,
1H), .delta. 7.24 (m, 4H), .delta. 7.16.about.7.09 (m, 3H), .delta.
6.98 (d, J=9.0 Hz, 2H), .delta. 6.72 (t, J=6.0 Hz, 1H), .delta.
6.60 (d, J=9.0 Hz, 2H), .delta. 6.62 (s, 13H), .delta.
5.65.about.5.56 (m, 2H), .delta. 5.37 (t, J=6.0 Hz, 1H), .delta.
5.09 (d, J=12.0 Hz, 1H), .delta. 4.92 (t, J=15.0 Hz, 2H), .delta.
4.63 (d, J=15.0 Hz, 1H), .delta. 4.49.about.4.31 (m, 2H), .delta.
3.86 (t, J=9.0 Hz, 1H), .delta. 3.59.about.3.27 (m, 7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-methoxy-phenyl)-pyridin-2-yl-
methyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0372] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.93 (d, J=9.0 Hz,
2H), .delta. 7.71 (t, J=6.0 Hz, 1H), .delta. 7.60 (d, J=9.0 Hz,
1H), .delta. 7.40.about.7.25 (m, 4H), .delta. 7.10 (d, J=6.0 Hz,
1H), .delta. 6.99 (t, J=9.0 Hz, 4H), .delta. 6.72 (t, J=6.0 Hz,
1H), .delta. 6.62 (d, J=9.0 Hz, 2H), .delta. 5.64.about.5.59 (m,
2H), .delta. 5.40 (t, J=6.0 Hz, 1H), .delta. 5.10.about.4.90 (m,
3H), .delta. 4.57 (d, J=15.0 Hz, 1H), .delta. 4.45.about.4.37 (m,
2H), .delta. 3.90 (t, J=9.0 Hz, 1H), .delta. 3.84 (s, 3H), .delta.
3.57.about.3.27 (m, 7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-methylsulfanyl-phenyl)-pyrid-
in-2-ylmethyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carbox-
ylic acid benzylamide
[0373] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.92 (d, J=9.0 Hz,
2H), .delta. 7.75.about.7.61 (m, 2H), .delta. 7.40.about.7,25 (m,
5H), .delta. 7.13 (d, J=9.0 Hz, 1H), .delta. 7.00 (d, J=9.0 Hz,
2H), .delta. 6.73 (t, J=6.0 Hz, 1H), .delta. 6.60 (t, J=9.0 Hz,
2H), .delta. 6.44 (s, 1H), .delta. 5.64.about.5.59 (m, 2H), .delta.
5.40 (t, J=6.0 Hz, 1H), .delta. 5.09 (d, J=12.0 Hz, 1H), .delta.
4.99.about.4.90 (m, 2H), .delta. 4.59 (d, J=15.0 Hz, 1H), .delta.
4.45.about.4.39 (m, 2H), .delta. 3.90 (t, J=9.0 Hz, 1H), .delta.
3.58.about.3.28 (m, 7H), .delta. 2.52 (s, 3H)
(6S,9aS)
2-allyl-8-(1-benzenesulfonyl-3-phenyl-1,1-indol-7-ylmethyl)-6-(4--
hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carbo-
xylic acid benzylamide
[0374] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.67 (s, 1H), 7.54
(m, 3H), 7.45.about.7.35 (m, 5H), 7.35.about.7.20 (m, 7H), 7.13 (d,
J=6.8 Hz, 3H), 6.96 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.4 Hz, 2H), 5.57
(m, 1H), 5.32.about.3.25 (m, dd, J=10.5, 5.7 Hz, 1H), 5.50 (m, 1H),
5.36 (d, J=5.7 Hz, 1H), 5.31 (d, J=16.2 Hz, 1H), 5.05 (d, J=10.3
Hz, 1H), 4.99 (d, J=4.5 Hz, 1H), 4.94 (d, J=3.1 Hz, 1H), 4.26 (ddd,
J=26.5, 15.0, 5.9 Hz, 2H), 3.50.about.3.20 (m, 6H), 3.05 (dd,
J=11.7, 4.0 Hz, 1H).
(6S,9aS)
2-allyl-8-[6-(3-cyano-phenyl)-pyridin-2-ylmethyl]-6-(4-hydroxy-be-
nzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0375] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.28.about.8.22
(m, 1H), .delta. 7.81 (t, J=9.0 Hz, 1H), .delta. 7.69.about.7.66
(m, 2H), .delta. 7.57 (t, J=9.0 Hz, 1H), .delta. 7.40.about.7.31
(m, 3H), .delta. 7.27.about.7.25 (m, 2H), .delta. 6.97 (d, J=9.0
Hz, 2H), .delta. 6.73 (t, J=6.0 Hz, 1H), .delta. 6.59 (t, J=9.0 Hz,
2H), .delta. 5.70.about.5.53 (m, 2H), .delta. 5.36 (t, J=6.0 Hz,
1H), .delta. 5.16.about.4.99 (m, 2H), .delta. 4.77 (d, J=6.0 Hz,
2H), .delta. 4.51.about.4.32 (m, 2H), .delta. 3.85 (t, J=9.0 Hz,
1H), .delta. 3.64.about.3.31 (m, 7H)
(6S,9aS)
2-allyl-8-(3-bromo-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahyd-
ro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
[0376] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.42.about.7.32
(m, 4H) .delta. 7.30.about.7.14 (m, 5H) .delta. 6.99.about.6.63 (m,
4H) .delta. 6.34 (s, 1H) .delta. 5.63.about.5.57 (m, 1H) .delta.
5.39.about.5.32 (m, 2H) .delta. 5.16 (d, J=10.2 Hz, 1H) .delta.
4.91 (dd, J=18.3 Hz, J=15.4 Hz, 2H) .delta. 4.41.about.4.36 (m, 4H)
.delta. 3.46 (d, J=6.1 Hz, 2H) .delta. 3.41 (d, J=4.5 Hz, 2H)
.delta. 3.35 (d, J=9.2 Hz, 2H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-phenyl-1H-indol-7-ylm-
ethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0377] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 10.09 (s, 1H),
7.87 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.3 Hz, 2H), 7.40.about.7.20 (m,
8H), 7.03 (t, J=7.5 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 6.89 (d, J=8.3
Hz, 1H), 6.53 (d, J=8.3 Hz, 2H), 6.43 (brs, OH), 5.51 (m, 1H),
5.42.about.5.27 (m, 2H), 5.21 (m, 1H), 5.09 (d, J=10.2 Hz, 1H),
4.90 (d, J=17.0 Hz, 1H), 4.42.about.4.20 (m, 3H), 3.40.about.3.30
(m, 5H), 3.16 (d, J=17.0 Hz, 1H).
(6S,9aS)
2-allyl-8-(6-cyclopropyl-pyridin-2-ylmethyl)-6-(4-hydroxy-benzyl)-
-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0378] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.49 (t, J=9.0 Hz,
1H), .delta. 7.39.about.7.24 (m, 3H), .delta. 7.03.about.6.92 (m,
4H), .delta. 6.85 (s, 1H), .delta. 6.73 (t, J=6.0 Hz, 1H), .delta.
6.63 (t, J=9.0 Hz, 2H), .delta. 5.70.about.5.53 (m, 2H), .delta.
5.32 (t, J=6.0 Hz, 1H), .delta. 5.20.about.5.10 (m, 2H), .delta.
4.83 (d, J=15.0 Hz, 1H), .delta. 4.48.about.4.32 (m, 3H), .delta.
3.77 (t, J=12.0 Hz, 1H), .delta. 3.55.about.3.29 (m, 1H), .delta.
2.01.about.1.19 (m, 1H), .delta. 0.95.about.0.93 (m, 4H)
(6S,9aS)
2-allyl-8-[2,3]bipyridinyl-6-ylmethyl-6-(4-hydroxy-benzyl)-4,7-di-
oxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0379] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.13 (s, 1H),
.delta. 8.56 (d, J=3.0 Hz, 1H), .delta. 8.27 (d, J=6.0 Hz, 1H),
.delta. 7.76 (t, J=6.0 Hz, 1H), .delta. 7.64 (d, J=9.0 Hz, 1H),
.delta. 7.39.about.7.19 (m, 6H), .delta. 6.92 (d, J=9.0 Hz, 2H),
.delta. 6.66 (t, J=6.0 Hz, 1H), .delta. 6.58 (d, J=9.0 Hz, 2H),
.delta. 5.60.about.5.55 (m, 2H), .delta. 5.44 (dd, J=3.0 Hz, J=12.0
Hz, 1H), .delta. 5.31 (t, J=6.0 Hz, 1H), .delta. 5.19 (d, J=9.0 Hz,
1H), .delta. 5.09 (d, J=15.0 Hz, 1H), .delta. 4.99 (dd, J=15.0 Hz,
J=27.0 Hz, 2H), .delta. 4.45.about.4.25 (m, 2H), .delta. 3.76 (t,
J=12.0 Hz, 1H), .delta. 3.58.about.3.26 (m, 7H)
CWP232066
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[2-(2-methoxy-phenyl)-pyridin-3-yl-
methyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0380] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.61 (d, J=4.7 Hz,
1H), .delta. 7.22.about.7.58 (m, 9H), .delta. 6.92.about.7.07 (m,
4H), .delta. 6.92.about.6.95 (m, 3H), .delta. 5.05.about.5.65 (m,
1H), .delta. 5.41 (d, J=8.0 Hz, 1H), .delta. 5.19.about.5.29 (m,
1H), .delta. 5.12 (t, J=11.0 Hz, 1H), .delta. 4.81.about.5.07 (m,
2H), .delta. 4.62 (q, J=15.2 Hz, 1H), .delta. 4.27.about.4.45 (m,
2H), .delta. 3.73 (d, J=13.7 Hz, 3H), .delta. 3.03.about.3.48 (m,
7H), .delta. 2.89.about.2.93 (m, 1H)
(6S,9aS)
2-allyl-8-(2-cyclopropyl-pyridin-3-ylmethyl)-6-(4-hydroxy-benzyl)-
-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0381] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.41 (d, J=3.6 Hz,
1H), .delta. 7.25.about.7.41 (m, 7H), .delta. 7.00.about.7.06 (m,
3H), .delta. 6.65.about.6.71 (m, 3H), .delta. 6.29 (s, 1H), .delta.
5.49.about.5.64 (m, 1H) .delta. 5.48 (dd, J=10.5 Hz, J=3.9 Hz 111),
.delta. 5.35 (t, J=5.5 Hz, 1H), .delta. 5.06.about.5.20 (m, 2H),
.delta. 4.92 (d, J=17.2 Hz, 1H), .delta. 4.45 (d, J=15.0 Hz, J=5.9
Hz, 1H), .delta. 4.35 (dd, J=15.0 Hz, J=5.9 Hz, 1H), .delta.
3.30.about.3.51 (m, 7H), .delta. 3.18 (dd, J=11.7 Hz, J=3.2 Hz,
1H), .delta. 2.02.about.2.18 (m, 1H), .delta. 1.14.about.1.23 (m,
1H), .delta. 0.93.about.1.02 (m, 3H).
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[6-(4-hydroxy-phenyl)-pyridin-2-yl-
methyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0382] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.82 (d, J=9.0 Hz,
2H), .delta. 7.66 (t, J=9.0 Hz, 1H), .delta. 7.51 (d, J=9.0 Hz,
1H), .delta. 7.38.about.7.22 (m, 4H), .delta. 7.05 (d, J=6.0 Hz,
1H), .delta. 6.99 (d, J=9.0 Hz, 4H), .delta. 6.84 (d, J=9.0 Hz,
2H), .delta. 6.73 (t, J=6.0 Hz, 1H), .delta. 6.63 (d, J=9.0 Hz,
2H), .delta. 5.67.about.5.51 (m, 2H), .delta. 5.44 (t, J=6.0 Hz,
1H), .delta. 5.06 (d, J=9.0 Hz, 1H), .delta. 4.41.about.4.36 (m,
2H), .delta. 3.85 (t, J=12.0 Hz, 1H), .delta. 3.53.about.3.25 (m,
7H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[6-(3-methoxy-phenyl)-pyridin-2-yl-
methyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0383] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.75.about.7.53
(m, 5H), .delta. 7.37.about.7.22 (m, 6H), .delta. 7.15 (d, J=9.0
Hz, 1H), .delta. 7.01 (d, J=6.0 Hz, 2H), .delta. 6.93 (d, J=9.0 Hz,
1H), .delta. 6.73 (t, J=6.0 Hz, 1H), .delta. 6.64 (d, J=9.0 Hz,
2H), .delta. 5.70.about.5.56 (m, 2H), .delta. 5.39 (t, J=6.0 Hz,
1H), .delta. 5.07.about.4.89 (m, 3H), .delta. 4.57 (d, J=15.0 Hz,
1H), .delta. 4.41.about.4.37 (m, 2H), 3.93.about.3.84 (m, 4H),
.delta. 3.53.about.3.26 (m, 7H)
(6S,9aS)
2-allyl-8-(3-cyano-1H-indol-7-ylmethyl)-6-(4-hydroxy-benzyl)-4,7--
dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0384] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 10.75 (s, 1H),
7.72 (m, 2H), 7.36.about.7.04 (m, 6H), 6.83 (d, J=8.4 Hz, 2H), 6.73
(t, J=6.0 Hz, 1H), 6.50 (d, J=8.4 Hz, 2H), 5.59 (m, 1H), 5.42 (t,
J=6.5 Hz, 1H), 5.24 (t, J=5.7 Hz, 1H), 5.14 (m, 1H), 5.10 (d,
J=17.1 Hz, 1H), 4.50.about.4.27 (m, 3H), 3.42.about.3.20 (m,
8H)
(6S,9aS)
2-allyl-8-(1-benzenesulfonyl-3-cyano-1H-indol-7-ylmethyl)-6-(4-hy-
droxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxy-
lic acid benzylamide
[0385] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.25 (s, 1H), 7.61
(d, J=7.6 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H),
7.35.about.7.15 (m, 7H), 6.96 (d, J=8.3 Hz, 2H), 6.92 (d, J=7.8 Hz,
1H), 5.73 (s, 1H), 5.57 (m, 1H), 5.45 (dd, J=1039, 3.5 Hz, 1H),
5.32 (t, J=5.4 Hz, 1H), 5.21.about.5.00 (m, 3H), 4.75 (d, J=16.2
Hz, 1H), 4.30 (ddd, J=36.6, 15.2, 6.4 Hz, 2H), 3.50.about.3.25 (m,
7H), 3.0 (dd, J=12.2, 3.6 Hz, 1H).
(6S,9aS)
2-allyl-842,39bipyridinyl-3-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dio-
xo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0386] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (d, J=2.0 Hz,
1H), .delta. 8.54.about.8.59 (m, 2H), .delta. 7.75 (d, J=7.9 Hz,
1H), 7.12.about.7.39 (m, 8H), .delta. 6.88 (d, J=8.4 Hz, 2H),
.delta. 6.55.about.6.60 (m, 3H), .delta. 5.46.about.5.56 (m, 1H),
.delta. 5.31 (dd, J=10.7 Hz, J=3.9 Hz, 1H), .delta. 5.17 (t, J=5.2
Hz, 1H), .delta. 5.07 (d, J=10.3 Hz, 1H), .delta. 4.96 (d, J=17.2
Hz, 1H), .delta. 4.83 (d, J=15.8 Hz, 1H), .delta. 4.45 (d, J=15.7
Hz, 1H), .delta. 4.31 (dd, J=14.9 Hz, J=6.0 Hz, 1H), .delta. 4.21
(dd, J=14.9 Hz, J=6.0 Hz, 1H), .delta. 3.17.about.3.41 (m, 7H),
.delta. 2.88 (dd, J=11.5 Hz, J=3.9 Hz, 1H). MS ESI 618.2 (M+H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-pyridin-3-yl-benzyl)--
hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0387] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.88 (s, 1H)
.delta. 8.63 (d, J=5.3 Hz, 1H) .delta. 7.93 (d, J=6.3 Hz, 1H)
.delta. 7.48 (d, J=5.7 Hz, 1H) .delta. 7.46.about.7.39 (m, 4H)
.delta. 7.36.about.7.26 (m, 5H) .delta. 7.22.about.6.94 (m, 4H)
.delta. 6.65 (s, 1H) .delta. 6.55 (d, J=11.2 Hz, 1H) .delta.
5.65.about.5.55 (m, 2H) .delta. 5.26 (s, 1H) .delta.
4.50.about.4.14 (dd, J=7.1 Hz, J=5.9 Hz, 2H) .delta. 4.82 (d,
J=10.6 Hz, 1H) .delta. 4.01 (d, J=15.2 Hz, 1H) .delta.
3.58.about.3.47 (m, 2H) .delta. 3.42.about.3.35 (m, 2H) .delta.
3.31.about.3.17 (m, 2H)
(6S,9aS)
2-allyl-8-[2-(3-cyano-phenyl)-pyridin-3-ylmethyl]-6-(4-hydroxy-be-
nzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0388] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.62 (d, J=4.2 Hz,
1H), .delta. 7.79 s, 1H), .delta. 7.70 (d, J=8.0 Hz, 3H), .delta.
7.55 (t, J=7.7 Hz, 1H), .delta. 7.45 (d, J=7.8 Hz, 1H), .delta.
7.21.about.7.38 (m, 5H), .delta. 6.95 (d, J=8.3 Hz, 1H), .delta.
6.60.about.6.69 (m, 3H), S 6.09 (s, 1H), .delta. 5.56.about.5.66
(m, 1H), .delta. 5.33 (dd, J=10.5 Hz, J=3.6 Hz, 1H), .delta. 5.24
(t, J=5.2 Hz, 1H), .delta. 5.16 (d, J=10.3 Hz, 1H), .delta. 5.05
(d, J=17.1 Hz, 1H), .delta. 4.85 (d, J=15.7 Hz, 1H), .delta. 4.50
(d, J=15.7 Hz, 1H), .delta. 4.40 (dd, J=14.9 Hz, J=5.9 Hz, 1H),
.delta. 4.29 (dd, J=14.9 Hz, J=5.9 Hz, 1H), .delta. 3.25.about.3.49
(m, 6H), .delta. 2.94 (dd, J=11.6 Hz, J=3.9 Hz, 1H). MS ESI 642.2
(M+H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-[2-(3-methoxy-phenyl)-pyridin-3-yl-
methyl]-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0389] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.60 (d, J=2.7 Hz,
1H), .delta. 7.46 (d, J=18.9 Hz, 1H), .delta. 7.20.about.7.37 (m,
7H), .delta. 6.94.about.7.03 (m, 5H), .delta. 6.59.about.6.63 (m,
2H), .delta. 6.55.about.6.60 (m, 3H), .delta. 6.24 (t, J=6.5 Hz,
1H), .delta. 5.63.about.5.77 (m, 3H), 5.15.about.5.23 (m, 2H),
.delta. 4.80 (dd, J=15.5 Hz, J=5.5 Hz, 1H), .delta. 4.29.about.4.67
(m, 4H), .delta. 3.83 (d, J=4.3 Hz, 3H), .delta. 3.16.about.3.42
(m, 6H), .delta. 2.79 (dd, J=11.5 Hz, J=3.9 Hz, 1H).
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-pyridin-4-yl-benzyl)--
hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0390] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.69 (d, J=6 Hz,
2H) .delta. 7.57 (d, J=6 Hz, 2H) .delta. 7.52.about.7.33 (m, 4H)
.delta. 7.31.about.7.29 (m, 5H) .delta. 7.26.about.6.96 (m, 4H)
.delta. 6.72 (s, 1H) .delta. 6.57 (d, J=8.2 Hz, 1H) .delta.
5.58.about.5.56 (m, 2H) .delta. 5.38 (d, J=7.1 Hz, 1H) .delta.
5.17.about.5.01 (dd, J=11.8 Hz, J=17.1 Hz, 2H) .delta.
4.75.about.4.31 (m, 4H) .delta. 3.50 (d, J=5.3 Hz, 2H) .delta.
3.46.about.3.41 (m, 2H) .delta. 3.35 (d, J=9.2 Hz, 2H)
(6S,9aS)
2-allyl-8-[6-(3,3-dimethyl-but-1-ynyl)-pyridin-2-ylmethyl]-6-(4-h-
ydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carbox-
ylic acid benzylamide
[0391] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.60 (t, J=9.0 Hz,
1H), .delta. 7.41.about.7.25 (m, 5H), .delta. 7.08 (d, J=9.0 Hz,
1H), .delta. 7.02 (d, J=9.0 Hz, 2H), .delta. 6.73 (t, J=6.0 Hz,
1H), .delta. 6.66 (d, J=9.0 Hz, 2H), .delta. 5.65.about.5.53 (m,
2H), .delta. 5.32 (t, J=6.0 Hz, 1H), .delta. 5.25.about.5.20 (m,
2H), .delta. 4.42.about.4.37 (m, 2H), .delta. 3.80 (t, J=12.0 Hz,
1H), .delta..delta. 3.60.about.3.29 (m, 7H), .delta. 1.33 (s,
9H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(1-propyl-1H-indol-3-ylm-
ethyl)-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0392] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.66 (d, J=7.5 Hz,
1H), 6.97-7.39 (m, 9H), 6.59-6.69 (m, 3H), 5.79 (s, 1H), 5.52 (m,
1H), 5.18-5.30 (m, 3H), 5.01 (d, J=10.8 Hz, 1H), 4.75 (d, J=17.4
Hz, 1H), 4.31-4.43 (m, 3H), 4.04 (t, J=6.3 Hz, 2H), 3.20-3.41 (m,
8H), 1.85 (q, J=7.5 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H)
Acetic acid 2-{3-[(6S,9aS)
2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyrazi-
no[2,1-c][1,2,4]triazin-8-ylmethyl]-indol-1-yl}-ethyl ester
[0393] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.66 (d, J=7.8 Hz,
1H) 6.96-7.36 (m, 9H), 6.58-6.68 (m, 3H), 6.73 (s, 1H), 5.50-5.56
(m, 1H), 5.24-5.34 (m, 2H), 5.06 (m, 2H), 4.81 (d, J=17.1 Hz, 1H),
4.56 (d, J=14.7 Hz, 1H), 4.28-4.45 (m, 6H), 3.22-3.44 (m, 8H), 2.00
(s, 3H)
(6S,9aS)
2-allyl-5-(4-hydroxy-benzyl)-4,6-dioxo-7-(2-phenyl-pyrimidin-4-yl-
methyl)-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid
benzylamide
[0394] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.75 (d, J=5.0
Hz, 1H), 8.42.about.8.39 (m, 2H), 7.47.about.7.45 (m, 3H),
7.39.about.7.25 (m, 5H), 7.04 (d, J=5.0 Hz, 1H), 6.98 (d, J=8.4 Hz,
2H), 6.73 (t, J=4.0 Hz, NH), 6.62 (d, J=8.4 Hz, 2H),
6.52.about.6.46 (brs, OH), 5.69.about.5.56 (m, 2H), 5.40 (t, J=5.6
Hz, 1H), 5.12 (d, J=10.1 Hz, 1H), 5.00 (d, J=17.2 Hz, 1H), 4.88 (d,
J=16.1 Hz, 1H), 4.58 (d, J=16.1 Hz, 1H), 4.60.about.4.33 (m, 2H),
3.92 (t, J=11.3 Hz, 1H), 3.60.about.3.33 (m, 7H)
(6S,9aS)
2-allyl-7-(2-amino-pyrimidin-4-ylmethyl)-5-(4-hydroxy-benzyl)-4,6-
-dioxo-octahydro-pyrido[3,4-c]pyridazine-1-carboxylic acid
benzylamide
[0395] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.18 (d, J=5.1
Hz, 1H), 7.40.about.7.23 (m, 5H), 6.83 (d, J=8.3 Hz, 2H), 6.73 (t,
J=6.0 Hz, NH), 6.59 (d, J=8.4 Hz, 2H), 6.46 (d, J=5.1 Hz, 1H),
5.75.about.5.62 (m, 1H), 5.56=5.46 (brs, NH2), 5.36 (dd, J=8.1 Hz
5.5 Hz, 1H), 5.23.about.5.17 (m, 3H), 5.01 (d, J=16.3 Hz, 1H),
4.49.about.4.25 (m, 2H), 3.91 (d, J=16.2 Hz, 1H), 3.70.about.3.37
(m, 7H), 3.29 (dd, J=13.8 Hz 5.6 Hz, 1H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-thiophen-3-yl-benzyl)-
-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0396] .sup.1H-NMR (300 MHz, TFA-d) S 7.53.about.7.47 (m, 3H)
.delta. 7.32.about.7.27 (m, 4H) .delta. 7.10.about.7.02 (m, 5H)
.delta. 6.97.about.6.94 (m, 4H) .delta. 6.65.about.6.62 (m, 3H)
.delta. 5.52.about.5.51 (m, 2H) .delta. 5.24.about.5.21 (m, 1H)
.delta. 5.07 (d, J=10.3 Hz, 2H) .delta. 4.60 (d, J=15.1 Hz, 2H)
.delta. 3.72 (d, J=18.2 Hz, 2H) .delta. 3.58.about.3.54 (m, 2H)
.delta. 3.49 (s, 2H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxo-8-(3-pyridin-2-yl-benzyl)--
hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0397] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.68 (d, J=5.1 Hz,
1H) .delta. 7.91 (d, J=11.2 Hz, 2H) .delta. 7.75 (d, J=11.2 Hz, 2H)
.delta. 7.46 (t, J=8.5 Hz, 1H) .delta. 7.29.about.7.22 (m, 5H)
.delta. 7.38.about.7.33 (m, 2H) .delta. 7.00.about.6.97 (m, 2H)
.delta. 6.68 (t, J=6.3 Hz, 1H) .delta. 6.62.about.6.59 (m, 3H)
.delta. 5.57.about.5.53 (m, 1H) .delta. 5.00.about.4.96 (dd, J=4.3
Hz, J=7.2 Hz, 2H) .delta. 4.41.about.4.33 (dd, J=6.2 Hz, J=6.3 Hz,
2H) .delta. 3.45.about.3.37 (m, 6H)
(6S,9aS)
2-allyl-8-(3'-cyano-biphenyl-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-
-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0398] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.3.23-3.29 (m, 4H),
3.31.about.3.44 (m, 4H), 4.24 (dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.35
(dd, J=5.9 Hz, J=14.9 Hz, 1H), 4.49 (d, J=14.8 Hz, 1H), 4.77 (d,
J=14.8 Hz, 1H), 4.91 (d, J=17 Hz, 1H), 5.05 (d, J=10.3 Hz, 1H),
5.28 (t, J=5.5 Hz, 1H), 5.38-5.41 (m, 1H), 5.52-5.58 (m, 1H), 6.53
(d, J=8.3 Hz, 2H), 6.66 (t, J=6 Hz, NH), 6.90 (d, J=8.3 Hz, 2H),
7.18-7.24 (m, 4H), 7.29 (dd, J=7.9 Hz, J=15.4 Hz, 1H), 7.38-7.43
(m, 3H), 7.47-7.52 (m, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.8
Hz, 1H), 7.80 (s, 1H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(3'-methoxy-biphenyl-3-ylmethyl)-4-
,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0399] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.51.about.7.40
(m, 4H) .delta. 7.37.about.7.30 (m, 5H) .delta. 7.24.about.7.22 (m,
4H) .delta. 7.19.about.6.88 (m, 4H) 6.65 (s, 1H) .delta. 6.56 (d,
J=9.0 Hz, 1H) .delta. 5.658.about.5.556 (m, 2H) .delta.
5.63.about.5.54 (m, 1H) .delta. 5.323.about.5.306 (m, 2H) .delta.
4.97.about.4.81 (dd, J=17.1 Hz, J=15.7 Hz, 2H) .delta.
4.40.about.4.30 (m, 2H) .delta. 3.85 (s, 3H) .delta. 3.43 (d,
J=10.3 Hz, 2H) .delta. 3.39.about.3.35 (m, 2H) .delta.
3.31.about.3.25 (m, 2H)
(6S,9aS)
2-allyl-6-(4-hydroxy-benzyl)-8-(2'-methoxy-biphenyl-3-ylmethyl)-4-
,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
[0400] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.47.about.7.37
(m, 4H) .delta. 7.35.about.7.29 (m, 5H) .delta. 7.28.about.7.15 (m,
4H) .delta. 7.05.about.6.96 (m, 4H) .delta. 6.69 (t, J=6.3 Hz, 1H)
.delta. 6.59 (d, J=9.2 Hz, 2H) .delta. 5.55.about.5.46 (m, 2H)
.delta. 5.10.about.5.04 (m, 2H) .delta. 4.40.about.4.34 (m, 2H)
.delta. 4.31.about.4.27 (m, 2H) .delta. 3.77 (s, 3H) .delta. 3.41
(d, J=7.1 Hz, 2H) .delta. 3.35 (d, J=6.6 Hz, 2H) .delta.
3.30.about.3.24 (dd, J=5.4 Hz, J=4.7 Hz, 2H)
(6S,9aS)
8-(3-Acetylbenzyl)-2-allyl-6-(4-hydroxy-benzyl)-4,7-dioxohexahydr-
opyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
[0401] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.60 (s, 3H),
3.24-3.52 (m, 9H), 4.31 (dd, J=6.0, 14.7 Hz, 1H), 4.42 (dd, J=6.0,
14.7 Hz, 1H), 4.57 (d, J=14.7 Hz, 1H), 4.80 (d, J=14.7 Hz, 1H),
5.03 (d, J=17.4 Hz, 1H), 5.14 (d, J=10.8 Hz, 1H), 5.33 (t, J=6.0
Hz, 1H), 5.43 (dd, J=4.2, 10.8 Hz, 1H), 5.55-5.66 (m, 1H), 6.62 (d,
J=8.4 Hz, 2H), 6.70 (t, J=6.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H),
7.22-7.32 (m, 5H), 7.34-7.39 (m, 2H), 7.44-7.49 (m, 2H), 7.83 (s,
1H), 7.88 (ddd, J=1.5, 11.5 Hz, 1H)
(6S,9aS)
2-allyl-8-[3-(6-fluoro-pyridin-3-yl)-benzyl]-6-(4-hydroxy-benzyl)-
-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
[0402] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.44 (d, J=4.0 Hz,
1H) .delta. 8.02.about.7.96 (m, 1H) .delta. 7.44.about.7.35 (m, 4H)
.delta. 7.31.about.7.16 (m, 9H) .delta. 7.04.about.7.01 (m, 1H)
.delta. 6.60 (s, 1H) .delta. 6.55 (d, J=8.2 Hz, 1H) .delta.
5.29.about.5.25 (m, 2H) .delta. 5.67.about.5.58 (m, 1H) .delta.
5.15.about.5.03 (m, 4H) .delta. 4.42.about.4.25 (m, 2H) .delta.
3.45 (s, 2H) .delta. 3.37.about.3.31 (dd, J=6.1 Hz, J=5.6 Hz, 2H)
.delta. 3.26.about.3.21 (dd, J=4.2 Hz, J=3.8 Hz, 2H)
(6S,9aS)
2-allyl-8-[1-benzenesulfonyl-2-(2-fluoro-phenyl)-3-methyl-1H-indo-
l-7-ylmethyl]-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2-
,4]triazine-1-carboxylic acid benzylamide
[0403] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.42-7.47 (m, 1H),
6.97-7.36 (m, 17H), 6.66-6.71 (m, 4H), 4.94-5.63 (m, 7H), 4.25-4.43
(m, 2H), 3.28-3.48 (m, 7H), 2.38 (s, 1H)
2-allyl-6-(4-hydroxy-benzyl)-8-(2'-hydroxy-biphenyl-3-ylmethyl)-4,7-dioxo
hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00506##
[0405] .sup.1H NMR (CDCl.sub.3): .delta. 7.806.about.7.765 (t,
J=6.2 Hz, 1H), .delta. 7.462.about.7.433 (d, J=8.5 Hz, 2H), .delta.
7.351.about.7.289 (m, 3 H), .delta. 7.234.about.7.165 (t, J=6.4 Hz,
3H), .delta. 7.144.about.7.119 (d, J=7.5 Hz, 1H), .delta.
7.045.about.7.020 (d, J=7.6 Hz, 1H), .delta. 6.941.about.6.915 (d,
J=7.9 Hz, 1H), .delta. 6.873.about.6.830 (t, J=6.6 Hz, 2H), .delta.
6.558.about.6.531 (d, J=8.3 Hz, 2H), .delta. 5.848.about.5.747 (m,
1H), .delta. 5.419.about.5.271 (dd, J=3.9 Hz, J=3.8 Hz, 1H),
.delta. 5.064.about.5.014 (d, J=9.2 Hz, 2H), .delta.
4.795.about.4.746 (d, J=14.8 Hz, 1H), .delta. 4.381.about.4.331 (d,
J=14.9 Hz, 1H), .delta. 4.290.about.4.127 (dd, J=6.6 Hz, J=6.6 Hz,
2H), .delta. 3.651.about.3.438 (m, 4H), .delta. 3.292 (s, 8H),
.delta. 3.126.about.3.108 (d, J=5.4 Hz, 2H)
3'-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyr-
azino[2,1-c][1,2,4]triazin-8-ylmethyl]-biphenyl-3-carboxylic
acid
##STR00507##
[0407] .sup.1H NMR (CDCl.sub.3): .delta. 8.237 (s, 1H), .delta.
8.076.delta.8.055 (d, J=3.6 Hz, 1H), .delta. 7.788.delta.7.644 (d,
J=7.2 Hz, 1H), .delta. 7.750 (s, 2H), .delta. 7.431.about.7.383 (t,
J=7.2 Hz, 2H), 7.311.about.7.232 (m, 6H), .delta. 7.201.about.6.161
(t, J=6.1 Hz, 3H), .delta. 6.946.about.6.919 (d, J=8.0 Hz, 2H),
.delta. 6.690.about.6.656 (t, J=5.1 Hz, 1H), .delta.
5.594.about.5.569 (d, J=7.8 Hz, 2H), 5.564 (m, 1H), .delta.
5.325.about.5.232 (m, 2H), .delta. 5.118.about.5.083 (d, J=10.4 Hz,
1H), .delta. 5.021.about.4.964 (d, J=17.1 Hz, 1H), .delta.
4.815.about.4.520 (dd, J=15.5 Hz, J=15.5 Hz, 2H), .delta.
4.356.about.4.341 (d, J=4.7 Hz, 2H), .delta. 3.500.about.3.243 (m,
8H)
2-allyl-8-(3-carbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-py-
razino[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
##STR00508##
[0409] .sup.1H NMR (CDCl.sub.3): .delta. 8.506 (s, 1H), .delta.
7.821.about.7.796 (d, J=7.6 Hz, 1H), .delta. 7.604 (s, 1H), .delta.
7.469.about.7.379 (m, 3
[0410] H), .delta. 7.346.about.7.320 (m, 2H), .delta.
7.234.about.7.210 (d, J=6.9 Hz, 2H), .delta. 7.010 (s, 1H), .delta.
6.9166.888 (d, J=8.5 Hz, 3H), .delta. 6.766.about.6.737 (d, J=8.5
Hz, 2H), .delta. 6.570.about.6.530 (t, J=6.0 Hz, 1H),
5.810.about.5.755 (d, J=16.6 Hz, 1H), .delta. 5.715.about.5.581 (m,
1H), .delta. 5.213.about.5.163 (m, 3H), .delta. 4.873.about.4.832
(dd, J=6.5 Hz, J=6.5 Hz, 1H), .delta. 3.892.about.3.837 (d, J=16.6
Hz, 1H), .delta. 3.633.about.3.576 (d, J=17.2 Hz, 2H), .delta.
3.504.about.3.283 (m, 6H)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(6-methoxy-pyridin-3-yl)-benzyl]-4,7-dio-
xo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00509##
[0412] .sup.1H NMR (CDCl.sub.3): .delta. 8.427.about.8.419 (d,
J=2.2 Hz, 1H), .delta. 8.846.about.8.809 (dd, J=2.5 Hz, J=2.5 Hz,
2H), 7.438.about.7.368 (m, 4H), .delta. 7.321.about.7.218 (m, 7H),
.delta. 7.166.about.7.145 (d, J=6.4 Hz, 1H), .delta.
6.989.about.6.961 (d, J=8.4 Hz, 2H), .delta. 6.891.about.6.862 (d,
J=8.6 Hz, 1H), .delta. 6.682.about.6.654 (d, J=8.4 Hz, 2H), .delta.
6.585.about.6.546 (t, J=5.7 Hz, 1H), .delta. 5.682.about.5.591 (dd,
J=10.3 Hz, J=10.3 Hz, 1H), 5.423.about.5.371 (d, J=15.4 Hz, 1H),
.delta. 5.277.about.5.247 (t, J=3.6 Hz, 1H), 5.171.about.5.133 (d,
J=11.4 Hz, 2H), .delta. 4.883.about.4.835 (dd, J=3.9 Hz, J=3.9 Hz,
1H), .delta. 4.504.about.4.432 (dd, J=6.8 Hz, J=6.8 Hz, 1H),
.delta. 4.218.about.4.105 (m, 2H), .delta. 4.045 (s, 3H) .delta.
3.573.about.3.516 (dd, J=3.1 Hz, J=3.1 Hz, 1H), .delta.
3.492.about.3.464 (d, J=8.5 Hz, 2H) .delta. 3.420.about.3.309 (m,
3H) .delta. 3.223.about.3.172 (dd, J=3.8 Hz, J=3.8 Hz, 1H)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(6-morpholin-4-yl-pyridin-3-yl)-benzyl]--
4,7-dioxo-hexahydro-pyrazino[2,1-c][1.2.4]triazine-1-carboxylic
acid benzylamide
##STR00510##
[0414] .sup.1H NMR (CDCl.sub.3): .delta. 8.30 (s, 1H), .delta.
7.390.about.7.314 (m, 3H), .delta. 7.250.about.7.213 (m, 11H),
.delta. 7.129 (s, 2H), .delta. 7.078.about.7.059 (d, J=5.6 Hz, 3H),
.delta. 6.933.about.6.905 (d, J=8.5 Hz, 3H), .delta.
6.741.about.6.711 (d, J=8.9 Hz, 2H), .delta. 6.620.about.6.592 (d,
J=8.4 Hz, 3H), .delta. 6.516.about.6.476 (t, J=6.0 Hz, 1H), .delta.
5.581 (m, 1H), .delta. 5.492.about.5.442 (d, J=15.5 Hz, 2H),
.delta. 5.520.about.5.186 (m, 1H), .delta. 5.126.about.5.039 (t,
J=16.9 Hz, 3H), .delta. 4.745.about.4.698 (dd, J=3.5 Hz, J=3.5 Hz,
1H), .delta. 4.461.about.4.390 (dd, J=6.6 Hz, J=6.6 Hz, 1H),
.delta. 4.159.about.4.092 (dd, J=5.4 Hz, J=5.4 Hz, 1H), .delta.
4.002.about.3.950 (d, J=15.5 Hz, 1H) .delta. 3.840.about.3.808 (m,
3H), .delta. 3.546.about.3.489 (m, 7H) .delta. 3.460.about.3.418
(t, J=6.2 Hz, 6H) .delta. 3.365.about.3.134 (m, 10H)
2-allyl-8-(3'-carbamoyl-biphenyl-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-diox-
o-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00511##
[0416] .sup.1H NMR (CDCl.sub.3): .delta. 8.043.about.8.018 (d,
J=7.6 Hz, 1H), .delta. 7.802 (s, 1H), .delta. 7.737.about.7.711 (d,
J=7.8 Hz, 1H), .delta. 7.621.about.7.536 (m, 2H), .delta.
7.492.about.7.345 (m, 4H), .delta. 7.260 (s, 7H), .delta.
7.142.about.7.118 (d, J=7.1 Hz, 2H), .delta. 7.075 (s, 1H), .delta.
6.921.about.6.893 (d, J=8.4 Hz, 2H), .delta. 6.651.about.6.611 (t,
J=6.0 Hz, 1H), .delta. 6.450.about.6.422 (d, J=8.4 Hz, 2H), .delta.
6.257 (s, 1H), .delta. 5.819.about.5.765 (d, J=16.1 Hz, 2H),
.delta. 5.697.about.5.638 (m, 1H), .delta. 5.251.about.5.201 (m,
3H), .delta. 5.050 (s, 1H), .delta. 4.398.about.4.170 (dd'dd, J=6.6
Hz, J=6.6 Hz, J=5.9 Hz, J=5.9 Hz, 2H), .delta. 3.929.about.3.875
(d, J=16.1 Hz, 1H), .delta. 3.647.about.3.381 (m, 8H)
6-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyra-
zino[2,1-c][1,2,4]triazin-8-ylmethyl]-pyridine-2-carboxylic acid
ethyl ester
##STR00512##
[0418] .sup.1H NMR (CDCl.sub.3): .delta. 8.030.about.8.005 (d,
J=7.1 Hz, 1H), .delta. 7.842.about.7.791 (t, J=7.7 Hz, 1H), .delta.
7.393.about.7.237 (m, 8H), .delta. 7.013.about.6.986 (d, J=8.4 Hz,
2H), .delta. 6.744.about.6.705 (t, J=5.9 Hz, 1H), .delta.
6.652.about.6.624 (d, J=8.4 Hz, 2H), .delta. 6.096 (s, 1H), .delta.
5.705.about.5.539 (m, 2H), .delta. 5.350.about.5.312 (t, J=5.6 Hz,
1H), .delta. 5.209.about.5.152 (m, 2H), .delta. 4.890.about.4.720
(dd, J=15.4 Hz, J=15.4 Hz, 2H), .delta. 4.472.about.4.307 (m, 4H),
.delta. 3.900.about.3.825 (t, J=11.4 Hz, 1H), .delta.
3.617.about.3.300 (m, 7H), .delta. 2.171 (s, 2H), .delta.
1.424.about.1.377 (t, J=3.3 Hz, 3H)
2-allyl-8-(5-carbamoyl-pyridin-3-ylmethyl)-6-(4-hydroxy-benzyl)-4,7-dioxo--
hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00513##
[0420] .sup.1H NMR (CDCl.sub.3): .delta. 8.977 (s, 1H), .delta.
8.634 (s, 1H), .delta. 7.623 (s, 1H), .delta. 7.419.about.7.304 (m,
4H), .delta. 7.262 (s, 2H), .delta. 7.216.about.7.193 (d, J=7.0 Hz,
2H), .delta. 6.884.about.6.856 (d, J=8.4 Hz, 2H), .delta.
6.695.about.6.667 (d, J=8.4 Hz, 2H), .delta. 6.619.about.6.578 (t,
J=6.0 Hz, 1H), 6.406 (s, 1H), .delta. 5.775.about.5.720 (d, J=16.4
Hz, 1H), .delta. 5.709.about.5.596 (m, 1H), 5.240.about.5.185 (m,
3H), 4.808.about.4.764 (dd, J=6.8 Hz, J=6.8 Hz, 1H), .delta.
4.421.about.4.155 (dd'dd, J=5.8 Hz, J=5.8 Hz, J=5.8 Hz, J=5.8 Hz,
2H), .delta. 3.899.about.3.845 (d, J=16.3 Hz, 1H), .delta.
3.504.about.3.283 (m, 7 II) .delta. 3.232.about.3.183 (dd, J=3.0
Hz, J=3.0 Hz, 1H),
2-allyl-6-(4-hydroxy-benzyl)-8-(3-methoxycarbamoyl-benzyl)-4,7-dioxo-hexah-
ydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00514##
[0422] .sup.1H NMR (CDCl.sub.3): .delta. 8.845.about.8.819 (d,
J=7.6 Hz, 1H), .delta. 7.504.about.7.208 (m, 5H), .delta.
7.261.about.7.233 (m, 4H), .delta. 6.925.about.6.897 (d, J=8.4 Hz,
3H), .delta. 6.777.about.6.749 (d, J=8.4 Hz, 2H), .delta.
6.636.about.6.595 (t, J=6.1 Hz, 1H), .delta. 5.849.about.5.794 (d,
J=16.6 Hz, 1H), .delta. 5.697.about.5.584 (m, 1H), .delta. 5.226
(s, 1H), .delta. 5.190.about.5.172 (d, J=5.6 Hz, 2H), .delta.
4.647.about.4.603 (dd, J=2.7 Hz, J=2.7 Hz, 1H), .delta.
4.507.about.4.124 (dd'dd, J=6.9 Hz, T=6.9 Hz, J=6.9 Hz, J=6.9 Hz,
2H), 3.789 (s, 3H), .delta. 3.680.about.3.243 (dd'dd, J=2.9 Hz,
J=2.9 Hz, J=2.9 Hz, J=2.9 Hz, 2H), .delta. 3.547 (s, 1H), .delta.
3.503.about.3.404 (m, 5H)
2-allyl-6-(4-hydroxy-benzyl)-8-(3-hydroxycarbamoyl-benzyl)-4,7-dioxo-hexah-
ydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00515##
[0424] .sup.1H NMR (CDCl.sub.3): .delta. 7.714 (s, 1H), .delta.
7.365.about.7.318 (t, J=6.7 Hz, 3H), .delta. 7.260 (m, 10H),
.delta. 6.910.about.6.778 (m, 4H), .delta. 6.708 (s, 1H), .delta.
6.543 (s, 1H), .delta. 5.847.about.5.792 (d, J=16.6 Hz, 1H),
.delta. 5.701.about.5.579 (m, 1H), 5.213.about.5.174 (d, J=11.7 Hz,
4H), .delta. 4.846.about.4.814 (d, J=8.2 Hz, 1H), .delta.
4.436.about.4.147 (dd, J=12.5 Hz, J=12.5 Hz, 2H), .delta.
3.771.about.3.713 (d, J=17.5 Hz, 2H), .delta. 3.645.about.3.210
(dd, J=16.5 Hz, J=16.5 Hz, 4H), .delta. 3.484.about.3.216 (m,
7H)
2-allyl-6-(4-hydroxy-benzyl)-8-[3-(2-hydroxy-ethylcarbamoyl)-benzyl]-4,7-d-
ioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00516##
[0426] .sup.1H NMR (CDCl.sub.3): .delta. 7.883.about.7.868 (d,
J=8.5 Hz, 1H), .delta. 7.465.about.7.269 (m, 6H), .delta. 7.225 (s,
4H), .delta. 7.176.about.7.152 (d, J=8.5 Hz, 2H), .delta. 7.049 (s,
1H), .delta. 6.660.about.6.502 (dd, J=2.7 Hz, J=2.7 Hz, 4H),
.delta. 5.704.about.5.570 (m, 1H), .delta. 5.503.about.5.451 (d,
J=6.1 Hz, 1H), .delta. 5.262 (s, 1H), .delta. 5.221.about.5.089
(dd, J=2.7 Hz, J=2.7 Hz, 2H), .delta. 4.817.about.4.772 (dd, J=2.7
Hz, J=2.7 Hz, 1H), .delta. 4.376.about.4.199 (dd'dd, J=6.9 Hz,
J=6.9 Hz, J=6.9 Hz, J=6.9 Hz, 2H), .delta. 4.159 (s, 1H), .delta.
3.816.about.3.178 (m, 13H)
2-allyl-8-(3-cyano-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazi-
no[2,1-c][1,2,4]triazine-1-carboxylic acid benzylamide
##STR00517##
[0428] .sup.1H NMR (CDCl.sub.3): .delta. 7.603.about.7.568 (m, 1H),
.delta. 7.436 (s, 1H), .delta. 7.376.about.7.352 (d, J=8.4 Hz, 2H),
.delta. 7.326.about.7.303 (d, J=6.8 Hz, 1H), .delta. 7.260 (s, 3H),
.delta. 7.237 (s, 1H), .delta. 6.991.about.6.963 (d, J=10.3 Hz,
2H), .delta. 6.712.about.6.684 (d, J=17.1 Hz, 2H), .delta.
5.659.about.5.637 (m, 1H), .delta. 5.332.about.5.280 (m, 2H),
5.211.about.5.177 (d, J=15.1 Hz, 1H), .delta. 5.116.about.5.059 (d,
J=5.4 Hz, 1H), .delta. 4.784.about.4.734 (d, J=5.9 Hz, 1H), .delta.
4.486.about.4.382 (dd, J=7.1 Hz, J=7.1 Hz, 2H), .delta.
4.158.about.4.086 (dd, J=6.6 Hz, J=6.6 Hz, 1H), .delta.
3.534.about.3.334 (m, 7H), .delta. 3.226.about.3.174 (dd, J=3.9 Hz,
J=3.9 Hz, 1H)
6-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyra-
zino[2,1-c][1,2,4]triazin-8-ylmethyl]-pyridine-2-carboxylic
acid
##STR00518##
[0430] .sup.1H NMR (CDCl.sub.3): .delta. 8.065.about.8.041 (d,
J=7.4 Hz, 1H), .delta. 7.973.about.7.922 (t, J=7.8 Hz, 1H), .delta.
7.415.about.7.389 (d, J=7.6 Hz, 1H), .delta. 7.344.about.7.201 (m,
5H), .delta. 6.940.about.6.912 (d, J=8.4 Hz, 2H), .delta.
6.657.about.6.629 (d, J=8.4 Hz, 2H), .delta. 5.853.about.5.762 (m,
1H), .delta. 5.466.about.5.418 (dd, J=3.8 Hz, J=3.8 Hz, 1H),
.delta. 5.253.about.5.102 (m, 3H), .delta. 4.921.about.4.619 (dd,
J=15.8 Hz, J=15.8 Hz, 2H), 4.317 (s, 2H), .delta. 4.129.about.4.057
(dd, J=7.2 Hz, J=7.2 Hz, 1H), .delta. 3.995.about.3.919 (t, J=11.5
Hz, 1H), .delta. 3.679.about.3.552 (m, 3H), .delta.
3.391.about.3.223 (m, 7H)
(6S,9aS)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-8-((6-carbamoylpyridin-2-yl-
)methyl)-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carbo-
xamide
##STR00519##
[0432] .sup.1H NMR (CDCl.sub.3): .delta. 8.190.about.8.165 (d,
J=7.5 Hz, 1H), 8.055 (m, 1H), 7.900.about.7.849 (t, J=7.5 Hz, 1H),
7.472.about.7.447 (d, J=7.5 Hz, 1H), 7.397.about.7.372 (d, J=7.5
Hz, 1H), 7.335.about.7.311 (d, 7.5 Hz, 1H), 7.271.about.7.247 (m,
4H), 6.636.about.6.596 (t, J=6.0 Hz, 1H), 6.575.about.6.547 (d,
J=8.4 Hz, 2H), 6.477.about.6.449 (d, J=8.4 Hz, 2H), 5.897 (m, 1H),
5.724.about.5.666 (m, 1H), 5.264.about.5.145 (m, 4H),
4.973.about.4.926 (dd, J=3.6, 10.5 Hz, 1H), 4.46.about.4.39 (dd,
J=6.0 Hz, 1H), 4.34.about.4.27 (dd, J=6.0 Hz, 1H),
4.030.about.4.021 (d, J=3.6 Hz, 1H), 3.996.about.3.928 (m, 1H),
3.778.about.3.705 (t, J=11.1 Hz, 1H), 3.705.about.3.383 (m, 5H),
3.302.about.3.238 (dd, J=5.4, 13.5 Hz, 1H)
(6S,9aS)-8-(3-(6-chloropyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-
-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carbox-
amide
##STR00520##
[0434] .sup.1H NMR (CDCl.sub.3): .delta. 8.632.about.8.624 (d,
J=2.4 Hz, 1H), 7.888.about.7.852 (dd, J=2.4, 8.1 Hz, 1H),
7.461.about.7.252 (m, 12H), 7.10 (s, 1H), 6.956.about.6.928 (d,
J=8.4 Hz, 2H), 6.607.about.6.579 (m, 3H), 5.671.about.5.580 (m,
1H), 5.288.about.5.256 (t, J=5.4 Hz, 1H), 5.188.about.5.024 (m,
4H), 4.474.about.4.403 (dd, J=6.3, 14.7 Hz, 1H), 4.353.about.4.302
(d, J=15.3 Hz, 1H), 4.251.about.4.202 (dd, J=6.3, 14.7 Hz, 1H),
3.530.about.3.217 (m, 8H)
(6S,9aS)-8-(3.about.cyano-4-fluorobenzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-b-
enzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxam-
ide
##STR00521##
[0436] .sup.1H NMR (CDCl.sub.3): .delta. 7.465.about.7.146 (m,
13H), 6.960.about.6.938 (d, J=6.6 Hz, 2H), 6.725.about.6.668 (m,
4H), 6.371.about.6.338 (m, 1H), 4.786.about.4.736 (d, J=1.5 Hz,
1H), 4.437.about.4.341 (m, 3H), 3.554.about.3.299 (m, 8H),
3.232.about.3.167 (tt, J=3.9, 8.1 Hz, 1H)
(6S,9aS)-8-(3-(1H-tetrazol-5-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-ben-
zyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamid-
e
##STR00522##
[0438] .sup.1H NMR (CDCl.sub.3): .delta. 7.953.about.7.927 (d,
J=7.8 Hz, 1H), 7.890 (m, 1H), 7.502.about.7.451 (t, J=7.8 Hz, 1H),
7.321.about.7.183 (m, 6H), 6.890.about.6.862 (d, J=7.8 Hz, 2H),
6.569.about.6.541 (d, J=7.8 Hz, 2H), 5.797.about.5.663 (m, 1H),
5.315.about.5.266 (dd, J=3.9, 10.8 Hz, 1H), 5.228.about.5.194 (t,
J=4.8 Hz, 1H), 5.035.about.4.964 (m, 2H), 4.808.about.4.759 (d,
J=14.7 Hz, 1H), 4.604.about.4.554 (d, J=14.7 Hz, 1H), 4.270 (m,
2H), 3.720.about.3.644 (t, J=11.4 Hz, 1H), 3.560.about.3.504 (m,
3H), 3.344.about.3.209 (m, 4H)
(6S,9aS)-8-(3-(2-methoxypyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl--
N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carbo-
xamide
##STR00523##
[0440] .sup.1H NMR (CDCl.sub.3): .delta. 8.180.about.8.157 (dd,
J=1.8, 5.1 Hz, 2H), 7.626.about.7.595 (dd, J=1.8, 5.1 Hz, 2H),
7.514.about.7.141 (m, 13H), 7.001.about.7.960 (m, 3H) m,
6.711.about.6.671 (t, J=6.0 Hz, 1H), 6.598.about.6.570 (m, 2H),
6.481 (m, 1H), 5.676.about.5.519 (m, 1H), 5.424.about.5.375 (dd,
J=4.2, 10.5 Hz, 1H), 5.336.about.5.299 (t, J=5.7 Hz, 1H),
5.110.about.5.074 (d, J=10.5 Hz, 1H), 4.980.about.4.915 (m, 2H),
4.469=4.286 (m, 4H), 3.947 (s, 3H), 3.470.about.3.246 (m, 9H)
(6S,9aS)-6-(4-hydroxy-benzyl)-2-allyl-8-((3-aminobenzo[d]isoxazol-5-yl)met-
hyl)-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)--
carboxamide
##STR00524##
[0442] .sup.1H NMR (CDCl.sub.3): .delta. 7.442.about.7.225 (m, 9H),
6.827.about.6.800 (d, J=8.1 Hz, 2H), 6.777.about.6.739 (t, J=8.1
Hz, 1H), 6.608.about.6.580 (d, J=8.1 Hz, 2H), 5.733.about.5.568 (m,
1H), 5.228.about.5.019 (m, 5H), 4.432.about.4.251 (m, 3H),
4.159.about.4.088 (dd, J=7.2, 14.4 Hz, 1H), 3.582.about.3.272 (m,
9H)
(6S,9aS)-8-(3-(N-Boc hyhdrazinic
carbonyl))benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-4,7-dioxo-hexahyd-
ro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
##STR00525##
[0444] .sup.1H NMR (CDCl.sub.3): .delta. 9.446 (s, 1H), 7.910 (m,
1H), 7.492.about.7.245 (m, 5H), 7.010 (s, 1H), 6.708.about.6.624
(m, 3H), 6.589.about.6.528 (t, J=6.3 Hz, 1H), 5.734.about.5.578 (m,
2H), 5.236.about.5.127 (m, 3H), 4.830.about.4.799 (d, J=6.3 Hz,
1H), 4.531.about.4.457 (q, J=7.2 Hz, 1H), 4.143.about.4.081 (dd,
J=3.9, 14.4 Hz, 1H), 3.820.about.3.767 (d, J=15.9 Hz, 1H),
3.585.about.3.299 (m, 7H), 1.384 (s, 9H)
(6S,9aS)-8-(3-(piperidine-1-carbonyl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl--
N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carbo-
xamide
##STR00526##
[0446] .sup.1H NMR (CDCl.sub.3): .delta. 7.407.about.7.178 (m,
10H), 6.949.about.6.921 (d, J=8.4 Hz, 2H), 6.854 (m, 1H),
6.680.about.6.633 (m, 3H), 5.669.about.5.578 (m, 1H),
5.298.about.5.050 (m, 4H), 4.705.about.4.580 (m, 2H),
4.440.about.4.369 (dd, J=6.3, 15.3 Hz, 1H), 4.350.about.4.280 (dd,
J=6.3, 15.3 Hz, 1H), 3.749.about.3.360 (m, 2H), 3.500.about.3.169
(m, 10H), 1.778 (m, 3H), 1.669 (m, 4H), 1.492 (m, 2H)
(6S,9aS)-8-(3-(pyrrolidine-1-carbonyl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-
-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carb-
oxamide
##STR00527##
[0448] .sup.1H NMR (CDCl.sub.3): .delta. 7.389.about.7.195 (m,
12H), 6.920.about.6.892 (d, J=8.4 Hz, 2H), 6.663.about.6.635 (d,
J=8.4 Hz, 2H), 5.635.about.5.579 (m, 1H), 5.271.about.5.240 (t,
J=4.8 Hz, 1H), 5.175.about.5.058 (m, 3H), 4.842.about.4.792 (d,
J=1.5 Hz, 1H), 4.466.about.4.272 (m, 3H), 3.675.about.3.632 (t,
J=6.3 Hz, 2H), 3.506.about.3.168 (m, 11H), 1.928 (m, 2H), 1.846 (m,
2H), 1.669 (m, 4H)
(6S,9aS)-8-(3-(2-fluoropyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-
-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carbox-
amide
##STR00528##
[0450] .sup.1H NMR (CDCl.sub.3): .delta. 8.201.about.8.185 (d,
J=4.8 Hz, 1H), 7.909=7.845 (m, 1H), 7.512=7.223 (m, 10H),
6.983.about.6.955 (d, J=8.4 Hz, 2H), 6.742.about.6.702 (t, J=6.0
Hz, 1H), 6.634.about.6.606 (d, J=8.4 Hz, 2H), 5.666.about.5.419 (m,
2H), 5.351.about.5.315 (t, J=4.8 Hz, 1H), 5.127.about.5.092 (d,
J=10.5 Hz, 1H), 4.999.about.4.946 (d, J=10.5 Hz, 1H),
4.463.about.4.291 (m, 3H), 3.490.about.3.278 (m, 7H)
(9aS)-8-(2-(1H-tetrazol-1-yl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benzyl-
-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
##STR00529##
[0452] .sup.1H NMR (CDCl.sub.3): .delta. 7.623.about.7.573 (t,
J=7.5 Hz, 1H), 7.518.about.7.470 (t, J=7.5 Hz, 1H),
7.392.about.7.230 (m, 7H), 6.930.about.6.902 (d, J=8.4 Hz, 2H),
6.779.about.6.739 (t, J=6.0 Hz, 1H), 6.676.about.6.658 (d, J=8.4
Hz, 2H), 5.659.about.5.602 (m, 1H), 5.407.about.5.359 (dd, J=6.3,
10.5 Hz, 1H), 5.237.about.5.113 (m, 3H), 4.694.about.4.641 (d,
J=15.9 Hz, 1H), 4.397.about.4.293 (m, 3H), 3.552.about.3.155 (m,
7H)
(6S,9aS)-8-(3-(benzylcarbamoyl)benzyl)-6-(4-hydroxy-benzyl)-2-allyl-N-benz-
yl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide
##STR00530##
[0454] .sup.1H NMR (CDCl.sub.3): .delta. 7.830.about.7.805 (d,
J=7.5 Hz, 1H), 7.760.about.7.714 (m, 1H), 7.447.about.7.014 (m,
12H), 6.847.about.6.817 (dd, J=2.7, 6.3 Hz, 2H), 6.629.about.6.601
(m, 2H), 6.553.about.6.512 (t, J=6.0 Hz, 1H), 5.700.about.5.582 (m,
1H), 5.534.about.5.480 (d, J=16.2 Hz, 1H), 5.205.about.5.024 (m,
4H), 4.279.about.4.212 (dd, J=4.5, 16.3 Hz, 1H), 4.070.about.3.879
(m, 3H), 3.636.about.3.311 (m, 7H)
(6S,9aS)-8-(3-(2-oxo-1,2-dihydropyridin-3-yl)benzyl)-6-(4-hydroxy-benzyl)--
2-allyl-N-benzyl-4,7-dioxo-hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6-
H)-carboxamide
##STR00531##
[0456] .sup.1H NMR (CDCl.sub.3): .delta. 7.620.about.7.555 (m, 2H),
7.504 (m, 1H), 7.390.about.7.166 (m, 6H), 6.905.about.6.878 (d,
J=8.1 Hz, 2H), 6.698.about.6.659 (t, J=6.0 Hz, 1H),
6.599.about.6.571 (d, J=8.1 Hz, 2H), 6.334.about.6.289 (t, J=6.0
Hz, 1H), 5.667.about.5.533 (m, 1H), 5.295.about.5.024 (m, 4H),
4.828.about.4.779 (d, J=14.7 Hz, 1H), 4.486.about.4.437 (d, J=14.7
Hz, 1H), 4.332.about.4.290 (t, J=6.3 Hz, 2H)
2-allyl-6-(4-hydroxy-benzyl)-8-(6-methylcarbamoyl-pyridin-2-ylmethyl)-4,7--
dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00532##
[0458] .sup.1H NMR (CDCl.sub.3): .delta. 8.205.about.8.180 (d,
J=7.7 Hz, 1H), 7.892.about.7.840 (t, J=7.8 Hz, 1H),
7.469.about.7.271 (m, 7H), 6.646.about.6.604 (t, J=6.1 Hz, 1H),
6.481.about.6.453 (d, J=8.5 Hz, 2H), 6.381.about.6.352 (d, J=8.5
Hz, 2H), 5.813.about.5.701 (td, J=10.2 Hz, J=6.5 Hz, 1H),
5.679.about.5.119 (m, 4H), 4.961.about.4.914 (dd, J=3.7 Hz, J=10.6
Hz, 1H), 4.498.about.4.317 (qd, J=15.0 Hz, J=6.2 Hz, 2H),
4.167.about.4.117 (dd, J=3.7 Hz, J=11.1 Hz, 1H), 3.927.about.3.222
(m, 9H), 2.983.about.2.966 (d, J=4.3 Hz, 3H)
2-allyl-6-(4-hydroxy-benzyl)-8-(3-methylcarbamoyl-benzyl)-4,7-dioxo-hexahy-
dro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00533##
[0460] .sup.1H NMR (CDCl.sub.3): .delta. 7.796.about.7.770 (d,
J=7.6 Hz, 1H), 7.444.about.7.221 (m, 9H), 6.911 (s, 1H),
6.827.about.6.799 (d, J=8.5 Hz, 2H), 6.648.about.6.620 (d, J=8.5
Hz, 2H), 5.813.about.5.701 (td, J=11.0 Hz, J=6.3 Hz, 1H),
5.623.about.5.569 (d, J=16.1 Hz, 1H), 5.246.about.5.191 (m, 4H),
5.050.about.5.006 (dd, J=3.0 Hz, J=10.3 Hz, 1H), 4.461.about.4.236
(qd, J=15.1 Hz, J=6.5 Hz, 2H), 3.938.about.3.884 (d, J=16.1 Hz,
1H), 3.686.about.3.314 (m, 8H), 2.949.about.2.934 (d, J=4.7 Hz,
3H)
2-allyl-8-[3-(2,5-dihydro-pyrrole-1-carbonyl)-benzyl]-6-(4-hydroxy-benzyl)-
-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
##STR00534##
[0462] .sup.1H NMR (CDCl.sub.3): .delta. 7.421.about.7.193 (m,
11H), 6.909.about.6.881 (d, J=8.4 Hz, 2H), 6.652.about.6.624 (d,
J=8.5 Hz, 2H), 6.624.about.6.582 (t, J=6.1 Hz, 1H),
5.623.about.5.836 (dd, J=2.0 Hz, J=4.4 Hz, 1H), 5.673.about.5.645
(m, 2H), 5.254.about.5.222 (t, J=4.8 Hz, 1H), 5.168.about.5.035 (m,
3H), 4.898.about.4.848 (d, J=15.1 Hz, 1H), 4.455.about.4.053 (m,
7H), 3.492.about.3.150 (m, 8H)
2-allyl-8-(3-dimethylcarbamoyl-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexa-
hydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00535##
[0464] .sup.1H NMR (CDCl.sub.3): .delta. 7.4027.235 (m, 9H), 7.168
(s, 1H), 6.931.about.6.914 (d, J=8.4 Hz, 2H), 6.658.about.6.642 (d,
J=8.4 Hz, 2H), 5.698.about.5.589 (td, J=16.6 Hz, J=6.2 Hz, 1H),
5.278.about.5.259 (t, J=4.8 Hz, 1H), 5.180.about.5.078 (m, 3H),
4.806.about.4.777 (d, J=15.0 Hz, 1H), 4.510.about.4.480 (d, J=15.0
Hz, 1H), 4.418.about.4.282 (qd, J=15.0 Hz, J=2.7 Hz, 2H),
3.530.about.3.300 (m, 7H), 3.204.about.3.173 (dd, J=3.8 Hz, J=11.7
Hz, 1H), 3.123 (s, 3H), 2.923 (s, 3H),
3-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyra-
zino[2,1-c][1,2,4]triazin-8-ylmethyl]-2-nitro-benzoic acid methyl
ester
##STR00536##
[0466] .sup.1H NMR (CDCl.sub.3): .delta. 7.961.about.7.945 (d,
J=7.6 Hz, 1H), 7.584.about.7.552 (t, J=7.8 Hz, 1H),
7.480.about.7.465 (d, J=7.6 Hz, 1H), 7.386.about.7.238 (m, 6H),
6.986.about.6.969 (d, J=8.3 Hz, 2H), 6.738.about.6.714 (t, J=5.9
Hz, 1H), 6.665.about.6.648 (d, J=8.3 Hz, 2H), 5.673.about.5.618
(td, J=10.2 Hz, J=4.0 Hz, 1H), 5.430.about.5.401 (dd, J=3.8 Hz,
J=10.8 Hz, 1H), 5.332.about.5.312 (t, J=5.2 Hz, 1H),
5.223.about.5.149 (d, J=10.3 Hz, 1H), 5.183.about.5.149 (d, J=17.1
Hz, 1H), 4.826.about.4.795 (d, J=15.7 Hz, 1H), 4.442.about.4.306
(m, 3H), 3.900 (s, 3H), 3.583.about.3.474 (m, 4H),
3.403.about.3.314 (m, 3H), 3.191.about.3.159 (dd, J=3.9 Hz, J=11.7
Hz, 1H),
2-allyl-8-(1-carbamoylmethyl-1H-benzoimidazol-4-ylmethyl)-6-(4-hydroxy-ben-
zyl)-4,7-dioxo-hexahydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic
acid benzylamide
##STR00537##
[0468] .sup.1H NMR (CDCl.sub.3): .delta. 7.610 (s, 1H),
7.321.about.7.220 (m, 5H), 7.132.about.7.117 (d, J=7.4 Hz, 2H),
6.878 (s, 1H), 6.685.about.6.662 (t, J=5.6 Hz, 1H),
6.635.about.6.619 (d, J=7.9 Hz, 2H), 6.328.about.6.313 (d, J=7.9
Hz, 2H), 6.223 (s, 1 H), 5.698.about.5.619 (td, J=16.7 Hz, J=6.3
Hz, 1H), 5.391.about.5.363 (d, J=14.2 Hz, 1H), 5.211.about.5.154
(m, 3H), 4.543 (s, 2H), 4.455.about.4.427 (d, J=14.3 Hz, 1H),
4.262.about.4.153 (qd, J=15.3 Hz, J=6.1 Hz, 2H), 3.912.about.3.894
(d, J=9.0 Hz, 1H), 6.635.about.6.619 (t, J=11.0 Hz, 1H),
3.486.about.3.345 (m, 4H), 3.201.about.3.345 (dd, J=5.3 Hz, J=13.3
Hz, 1H),
2-allyl-8-(3-carbamoyl-2-nitro-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexa-
hydro-pyrazino[2,1-c][1,2,4]triazine-1-carboxylic acid
benzylamide
##STR00538##
[0470] .sup.1H NMR (CDCl.sub.3): .delta. 7.655.about.7.565 (m, 2H),
7.348.about.7.565 (m, 6H), 6.939.about.6.911 (d, J=8.5 Hz, 2H),
6.691.about.6.663 (d, J=8.5 Hz, 2H), 5.861.about.5.726 (td, J=16.8
Hz, J=6.4 Hz, 1H), 5.436.about.5.388 (dd, J=3.7 Hz, J=10.7 Hz, 1H),
5.225.about.4.976 (m, 4H), 4.342.about.4.289 (m, 3H),
3.767.about.3.692 (t, J=11.5 Hz, 1H)
{4-[2-allyl-1-benzylcarbamoyl-6-(4-hydroxy-benzyl)-4,7-dioxo-octahydro-pyr-
azino[2,1-c][1,2,4]triazin-8-ylmethyl]-benzyl}-phosphonic acid
##STR00539##
[0472] .sup.1H NMR (DMSO-D6): .delta. 8.176 (s, 3H),
7.805.about.7.769 (t, J=5.6 Hz, 1H), 7.362.about.7.189 (m, 7H),
7.031.about.7.005 (d, J=7.5 Hz, 2H), 6.829.about.6.801 (d, J=8.2
Hz, 2H), 6.551.about.6.525 (d, J=8.2 Hz, 2H), 5.887.about.5.751 (m,
1H), 5.267.about.5.092 (m, 3H), 5.024.about.4.992 (t, J=4.8 Hz,
2H), 4.910.about.4.859 (d, J=15.4 Hz, 1H), 4.282.about.4.152 (m,
2H), 4.038.about.3.975 (m, 1H), 3.691.about.3.487 (m, 4H),
3.286.about.2.814 (m, 6H).
[0473] The libraries of the present invention were screened for
bioactivity by various techniques and methods. In general, the
screening assay may be performed by (1) contacting the mimetics of
a library with a biological target of interest, such as a receptor,
to allow binding between the mimetics of the library and the target
to occur, and (2) detecting the binding event by an appropriate
assay, such as the calorimetric assay disclosed by Lam et al.
(Nature 354:82-84, 1991) or Griminski et al. (Biotechnology
12:1008-1011, 1994) (both of which are incorporated herein by
reference). In a preferred embodiment, the library members are in
solution and the target is immobilized on a solid phase.
Alternatively, the library may be immobilized on a solid phase and
may be probed by contacting it with the target in solution.
[0474] Inhibition activity against Wnt signaling was measured by
the TopFlash reporter. The lower IC50 value means the higher
inhibition activity. A compound can be classified as active if IC50
is 10 .mu.M or below. When IC50 is 5.about.10 .mu.M, the compound
can be a candidate for a pharmaceutical. A compound is deemed
strong if IC50 is 1.about.5 .mu.M, and a compound is deemed very
strong if IC50 is 1 .mu.M or below.
[0475] Most of the compounds of the present invention showed IC50
of 5 .mu.M or below, that means they have strong inhibition
activity against Wnt signaling.
[0476] Table 3 below shows compounds for bioactivity test selected
from the library of the present invention and IC50 values thereof,
which were measured by the Reporter gene assay as described in
Example 2.
TABLE-US-00003 IC50 (.mu.M) MEASURED BY TopFlash REPORTER GENE
ASSAY OF SELECTED LIBRARY COMPOUNDS M.W. RGA, IC50 (.mu.M) NO
Structure Formula TopF 1 ##STR00540## 800.92 C44H44N6O7S 0.081 .+-.
0.0086 2 ##STR00541## 774.88 C42H42N6O7S 0.084 .+-. 0.016 3
##STR00542## 620.70 C35H36N6O5 0.098 .+-. 0.014 4 ##STR00543##
646.73 C37H38N6O5 0.14 .+-. 0.025 5 ##STR00544## 612.68 C33H36N6O6
0.16 .+-. 0.08 6 ##STR00545## 795.30 C41H39ClN6O7S 0.18 .+-. 0.076
7 ##STR00546## 634.70 C36H35FN6O4 0.26 .+-. 0.08 8 ##STR00547##
634.70 C36H35FN6O4 0.27 .+-. 0.03 9 ##STR00548## 624.73 C35H40N6O5
0.30 .+-. 0.02 10 ##STR00549## 654.76 C39H38N6O4 0.30 .+-. 0.06 11
##STR00550## 743.83 C40H37N7O6S 0.31 .+-. 0.09 12 ##STR00551##
616.71 C36H36N6O4 0.34 .+-. 0.12 13 ##STR00552## 753.65
C37H34N5Na2O8P 0.36 .+-. 0.13 14 ##STR00553## 735.66
C32H32N7Na2O7PS 0.37 .+-. 0.07 15 ##STR00554## 859.60
C32H31N7Na4O10P2S 0.37 .+-. 0.07 16 ##STR00555## 636.51
C31H31BrFN5O4 0.39 .+-. 0.05 17 ##STR00556## 585.72 C32H35N5O4S
0.42 .+-. 0.04 18 ##STR00557## 672.77 C39H40N6O5 0.42 .+-. 0.12 19
##STR00558## 613.11 C33H33ClN6O4 0.43 .+-. 0.08 20 ##STR00559##
753.27 C39H37ClN6O6S 0.43 .+-. 0.10 21 ##STR00560## 613.71 0.45
.+-. 0.05 22 ##STR00561## 778.70 C39H37N6Na2O7P 0.45 .+-. 0.29 23
##STR00562## 622.74 C34H34N6O4S 0.47 .+-. 0.13 24 ##STR00563##
734.68 0.48 .+-. 0.11 25 ##STR00564## 636.74 C36H40N6O5 0.52 .+-.
0.04 26 ##STR00565## 629.70 C37H35N5O5 0.52 .+-. 0.048 27
##STR00566## 794.92 C45H42N6O6S 0.52 .+-. 0.09 28 ##STR00567##
634.70 C36H35FN6O4 0.52 .+-. 0.06 29 ##STR00568## 699.78
C35H37N7O7S 0.53 .+-. 0.24 30 ##STR00569## 584.62 C31H32N6O6 0.54
.+-. 0.06 31 ##STR00570## 723.62 C33H36N5Na2O9P 0.54 .+-. 0.08 32
##STR00571## 640.72 0.56 .+-. 0.07 33 ##STR00572## 634.70
C36H35FN6O4 0.56 .+-. 0.44 34 ##STR00573## 616.71 C36H36N6O4 0.58
.+-. 0.132 35 ##STR00574## 719.65 C33H32N5Na2O7PS 0.59 .+-. 0.066
36 ##STR00575## 595.71 C33H33N5O4S 0.59 .+-. 0.10 37 ##STR00576##
636.70 C34H36N8O5 0.60 .+-. 0.13 38 ##STR00577## 664.79 C38H44N6O5
0.61 .+-. 0.09 39 ##STR00578## 700.86 0.61 .+-. 0.19 40
##STR00579## 631.72 C36H37N7O4 0.63 .+-. 0.06 41 ##STR00580##
683.58 C32H29Cl2FN6O4S 0.63 .+-. 0.09 42 ##STR00581## 709.66
C32H34N5Na2O7PS 0.66 .+-. 0.0079 43 ##STR00582## 630.17 0.66 .+-.
0.06 44 ##STR00583## 638.71 C34H31FN6O4S 0.67 .+-. 0.05 45
##STR00584## 668.77 0.67 .+-. 0.09 46 ##STR00585## 597.66
C33H35N5O6 0.69 .+-. 0.15 47 ##STR00586## 732.86 0.69 .+-. 0.19 48
##STR00587## 597.66 C32H35N7O5 0.7 .+-. 0.26 49 ##STR00588## 579.65
C32H33N7O4 0.71 .+-. 0.43 50 ##STR00589## 623.72 C33H33N7O4S 0.72
.+-. 0.075 51 ##STR00590## 694.9 0.72 .+-. 0.15 52 ##STR00591##
618.52 C31H32BrN5O4 0.73 .+-. 0.09 53 ##STR00592## 678.80
C37H38N6O5S 0.73 .+-. 0.03 54 ##STR00593## 650.77 C37H42N6O5 0.74
.+-. 0.05 55 ##STR00594## 700.86 0.74 .+-. 0.08 56 ##STR00595##
672.77 C39H40N6O5 0.74 .+-. 1.46 57 ##STR00596## 582.26 C32H34N6O5
0.76 .+-. 0.12 58 ##STR00597## 605.63 C32H33F2N5O5 0.78 .+-. 0.13
59 ##STR00598## 640.72 0.78 .+-. 0.15 60 ##STR00599## 658.75
C38H38N6O5 0.79 .+-. 0.10 61 ##STR00600## 616.71 C36H36N6O4 0.80
.+-. 0.07 62 ##STR00601## 701.81 C40H43N7O5 0.81 .+-. 0.15 63
##STR00602## 826.93 C46H43FN6O6S 0.82 .+-. 0.25 64 ##STR00603##
732.85 C40H40N6O6S 0.82 .+-. 0.33 65 ##STR00604## 578.66 C33H34N6O4
0.83 .+-. 0.22 66 ##STR00605## 652.82 0.84 .+-. 0.09 67
##STR00606## 592.69 C34H36N6O4 0.85 .+-. 0.089 68 ##STR00607##
610.74 0.86 .+-. 0.09 69 ##STR00608## 582.62 C32H31FN6O4 0.87 .+-.
0.32 70 ##STR00609## 686.77 C37H43FN6O6 0.9 .+-. 0.2 71
##STR00610## 621.73 C35H39N7O4 0.9 .+-. 0.08 72 ##STR00611## 621.75
C35H35N5O4S 0.90 .+-. 0.13 73 ##STR00612## 581.66 C33H35N5O5 0.90
.+-. 0.27 74 ##STR00613## 593.6 C31H30F3N5O4 0.91 .+-. 0.11 75
##STR00614## 640.72 0.92 .+-. 0.14 76 ##STR00615## 636.74
C36H40N6O5 0.94 .+-. 0.04 77 ##STR00616## 782.64 C33H3OFN6Na2O9PS
0.94 .+-. 0.07 78 ##STR00617## 554.64 C31H34N6O4 0.95 .+-. 0.15 79
##STR00618## 639.74 C36H41N5O6 0.95 .+-. 0.21 80 ##STR00619##
650.67 C32H29F3N6O4S 0.96 .+-. 0.13 81 ##STR00620## 646.74
C37H38N6O5 0.97 .+-. 0.18 82 ##STR00621## 630.74 C37H38N6O4 0.99
.+-. 0.14 83 ##STR00622## 620.70 C35H36N6O5 0.99 .+-. 0.24 84
##STR00623## 594.66 C32H34N8O4 1 .+-. 0.25 85 ##STR00624## 652.77
1.0 .+-. 0.22 86 ##STR00625## 767.29 C40H39ClN6O6S 1.0 .+-. 0.25 87
##STR00626## 607.66 C34H33N5O6 1.01 .+-. 0.24 88 ##STR00627##
733.84 C39H39N7O6S 1.02 .+-. 0.11 89 ##STR00628## 625.76 C36H43N5O5
1.03 .+-. 0.11 90 ##STR00629## 625.71 C35H39N5O6 1.03 .+-. 0.16 91
##STR00630## 640.73 C35H40N6O6 1.04 .+-. 0.18 92 ##STR00631##
703.59 C32H32N7Na2O7P 1.04 .+-. 0.18 93 ##STR00632## 661.67
C34H34F3N7O4 1.07 .+-. 0.2 94 ##STR00633## 746.66 C35H37N6Na2O8P
1.09 .+-. 0.16 95 ##STR00634## 580.68 C33H36N6O4 1.10 .+-. 0.12 96
##STR00635## 608.73 C35H40N6O4 1.11 .+-. 0.25 97 ##STR00636##
582.62 C32H31FN6O4 1.13 .+-. 0.05 98 ##STR00637## 646.74 C37H38N6O5
1.17 .+-. 0.15 99 ##STR00638## 736.82 C39H44N8O7 1.17 .+-. 0.27 100
##STR00639## 610.74 1.21 .+-. 0.14 101 ##STR00640## 678.82
C39H46N6O5 1.24 .+-. 0.07 102 ##STR00641## 596.68 C33H36N6O5 1.25
.+-. 0.21 103 ##STR00642## 628.72 C33H33FN6O4S 1.26 .+-. 0.19 104
##STR00643## 634.75 C31H31FN6O4S2 1.27 .+-. 0.10 105 ##STR00644##
760.26 C38H38ClN5O8S 1.27 .+-. 0.24 106 ##STR00645## 666.77
C37H42N6O6 1.28 .+-. 0.10 107 ##STR00646## 620.72 C30H29FN6O4S2 1.3
.+-. 0.2 108 ##STR00647## 580.68 C33H36N6O4 1.31 .+-. 0.33 109
##STR00648## 626.7 C34H38N6O6 1.35 .+-. 0.15 110 ##STR00649##
877.21 C39H36ClN6Na2O9PS 1.39 .+-. 0.36 111 ##STR00650## 638.75
1.41 .+-. 0.21 112 ##STR00651## 732.67 C35H39N6Na2O7P 1.41 .+-.
0.21 113 ##STR00652## 596.68 C33H36N6O5 1.41 .+-. 0.38 114
##STR00653## 650.77 C37H42N6O5 1.42 .+-. 0.51 115 ##STR00654##
631.72 C37H37N5O5 1.43 .+-. 0.27 116 ##STR00655## 620.74 C36H40N6O4
1.43 .+-. 0.26 117 ##STR00656## 604.10 C32H34ClN5O5 1.44 .+-. 0.22
118 ##STR00657## 679.79 C36H37N7O5S 1.47 .+-. 0.19 119 ##STR00658##
749.70 C36H42N5Na2O8P 1.51 .+-. 0.16 120 ##STR00659## 587.64
C32H34FN5O5 1.51 .+-. 0.34 121 ##STR00660## 646.74 C37H38N6O5 1.53
.+-. 0.17 122 ##STR00661## 617.14 C33H37ClN6O4 1.54 .+-. 0.07
123 ##STR00662## 595.69 C34H37N5O5 1.55 .+-. 0.21 124 ##STR00663##
619.62 C32H31F2N5O6 1.56 .+-. 0.33 125 ##STR00664## 619.51
C30H31BrN6O4 1.57 .+-. 0.29 126 ##STR00665## 640.73 C38H36N6O4 1.58
.+-. 0.27 127 ##STR00666## 645.75 C38H39N5O5 1.61 .+-. 0.31 128
##STR00667## 658.79 C39H42N6O4 1.61 .+-. 0.59 129 ##STR00668##
648.55 C32H34BrN5O5 1.64 .+-. 0.27 130 ##STR00669## 690.83
C40H46N6O5 1.66 .+-. 0.18 131 ##STR00670## 642.66 C33H34N6O8 1.66
.+-. 0.27 132 ##STR00671## 564.63 C32H32N6O4 1.71 .+-. 0.28 133
##STR00672## 743.56 C32H30F2N5Na2O9P 1.73 .+-. 0.22 134
##STR00673## 646.74 C37H38N6O5 1.73 .+-. 0.35 135 ##STR00674##
696.84 C39H48N6O6 1.77 .+-. 0.15 136 ##STR00675## 719.63
C34H36N5Na2O8P 1.83 .+-. 0.32 137 ##STR00676## 645.75 C38H39N5O5
1.86 .+-. 0.30 138 ##STR00677## 728.04 C32H33ClN5Na2O8P 1.86 .+-.
0.38 139 ##STR00678## 653.77 C37H43N5O6 1.89 .+-. 0.38 140
##STR00679## 645.75 C38H39N5O5 1.91 .+-. 0.24 141 ##STR00680##
634.70 C36H35FN6O4 1.91 .+-. 0.28 142 ##STR00681## 652.77 1.92 .+-.
0.28 143 ##STR00682## 651.79 C38H45N5O5 1.93 .+-. 0.18 144
##STR00683## 615.72 C37H37N5O4 1.94 .+-. 0.48 145 ##STR00684##
595.69 C34H37N5O5 1.96 .+-. 0.27 146 ##STR00685## 631.72 C37H37N5O5
1.99 .+-. 0.12 147 ##STR00686## 619.11 C32H35ClN6O5 1.99 .+-. 0.32
148 ##STR00687## 632.71 C36H36N6O5 10.01 .+-. 1.7 149 ##STR00688##
565.66 C33H35N5O4 10.13 .+-. 2.38 150 ##STR00689## 681.86
C40H51N5O5 10.15 .+-. 1.55 151 ##STR00690## 668.71 C32H34F2N6O6S
10.19 .+-. 2.3 152 ##STR00691## 629.70 C34H39N507 10.78 .+-. 1.9
153 ##STR00692## 583.64 C31H33N7O5 10.8 .+-. 1.97 154 ##STR00693##
625.76 C36H43N5O5 11.8 .+-. 0.9 155 ##STR00694## 667.79 11.85 .+-.
1.61 156 ##STR00695## 632.71 C36H36N6O5 12.16 .+-. 2.02 157
##STR00696## 620.72 C33H32N8O3S 12.41 .+-. 2.36 158 ##STR00697##
632.68 C32H30F2N6O4S 12.47 .+-. 2.66 159 ##STR00698## 620.74
C36H40N6O4 14.05 .+-. 2.30 160 ##STR00699## 597.66 C32H35N7O5 14.23
.+-. 2.05 161 ##STR00700## 761.93 C40H51N5O8S 14.42 .+-. 2.77 162
##STR00701## 638.74 C33H34N8O4S 15.10 .+-. 3.34 163 ##STR00702##
651.84 C39H49N5O4 15.67 .+-. 1.87 164 ##STR00703## 607.66
C32H33N9O4 15.69 .+-. 3.22 165 ##STR00704## 646.74 C37H38N6O5 17.21
.+-. 4.11 166 ##STR00705## 672.75 C39H37FN6O4 17.54 .+-. 5.57 167
##STR00706## 724.61 C32H35N6Na2O9P 19.41 .+-. 3.40 168 ##STR00707##
583.64 C31H33N7O5 2.01 .+-. 0.20 169 ##STR00708## 595.69 C34H37N5O5
2.01 .+-. 0.34 170 ##STR00709## 714.23 C37H36ClN5O6S 2.07 .+-. 0.43
171 ##STR00710## 732.67 C35H39N6Na2O7P 2.10 .+-. 0.34 172
##STR00711## 792.73 C37H43N6Na2O9P 2.21 .+-. 0.35 173 ##STR00712##
696.84 C39H48N6O6 2.26 .+-. 0.16 174 ##STR00713## 732.85
C40H40N6O6S 2.33 .+-. 0.64 175 ##STR00714## 599.68 C33H37N5O6 2.36
.+-. 0.57 176 ##STR00715## 617.70 C35H35N7O4 2.37 .+-. 0.22 177
##STR00716## 619.51 C30H31BrN6O4 2.37 .+-. 0.35 178 ##STR00717##
856.79 C40H39N6Na2O9PS 2.38 .+-. 0.75 179 ##STR00718## 662.80
C37H38N6O4S 2.42 .+-. 0.32 180 ##STR00719## 646.73 C37H38N6O5 2.42
.+-. 0.47 181 ##STR00720## 632.73 C32H36N6O6S 2.47 .+-. 0.37 182
##STR00721## 612.68 C33H36N6O6 2.48 .+-. 0.22 183 ##STR00722##
596.68 C33H36N6O5 52.5 .+-. 0.32 184 ##STR00723## 623.70 C35H37N5O6
2.56 .+-. 0.29 185 ##STR00724## 638.75 2.61 .+-. 0.19 186
##STR00725## 616.71 C36H36N6O4 2.66 .+-. 0.74 187 ##STR00726##
655.75 C38H37N7O4 2.67 .+-. 0.28 188 ##STR00727## 617.72
C32H35N5O6S 2.67 .+-. 0.59 189 ##STR00728## 636.74 C36HN6O5 2.68
.+-. 0.48 190 ##STR00729## 676.74 C32H36N8O7S 2.79 .+-. 0.24 191
##STR00730## 641.72 C37H35N7O4 2.81 .+-. 0.52 192 ##STR00731##
599.66 C30H29N7O5S 2.85 .+-. 0.79 193 ##STR00732## 587.64
C321134FN5O5 2.86 .+-. 0.49 194 ##STR00733## 612.68 C33H36N6O6 2.89
.+-. 0.50 195 ##STR00734## 653.76 20.91 .+-. 3.94 196 ##STR00735##
589.63 C32H33F2N5O4 21.2 .+-. 2.15 197 ##STR00736## 611.69
C33H37N7O5 21.77 .+-. 3.69 198 ##STR00737## 617.70 C35H35N7O4 22.25
.+-. 5.69 199 ##STR00738## 692.85 C39H48N8O4 25.9 .+-. 3.38 200
##STR00739## 790.99 25.92 .+-. 4.72 201 ##STR00740## 653.76 26.10
.+-. 7.10 202 ##STR00741## 689.21 28.76 .+-. 5.69 203 ##STR00742##
725.57 C33H36N5O6 3.03 .+-. 0.36 204 ##STR00743## 713.78 C40H39N7O6
3.13 .+-. 0.44 205 ##STR00744## 579.65 C32H33N7O4 3.14 .+-. 0.68
206 ##STR00745## 610.74 3.18 .+-. 0.75 207 ##STR00746## 582.65
C32H34N6O5 3.25 .+-. 0.41 208 ##STR00747## 646.74 C37H38N6O5 3.27
.+-. 0.80 209 ##STR00748## 605.69 C34H35N7O4 3.3 .+-. 0.58 210
##STR00749## 697.78 C37H43N707 3.57 .+-. 0.89 211 ##STR00750##
732.85 C40H40N6O6S 3.61 .+-. 0.47 212 ##STR00751## 652.74
C36H40N6O6 3.62 .+-. 0.63 213 ##STR00752## 683.80 C40H41N7O4 3.62
.+-. 0.65 214 ##STR00753## 611.73 C35H41N5O5 3.72 .+-. 0.47 215
##STR00754## 595.65 C32H33N7O5 3.75 .+-. 0.32 216 ##STR00755##
711.58 C32H33FN5Na2O8P 3.8 .+-. 1.1 217 ##STR00756## 617.70
C35H35N7O4 3.87 .+-. 0.45 218 ##STR00757## 646.74 C37H38N6O5 3.96
.+-. 0.93 219 ##STR00758## 682.23 C37H36ClN5O4S 3.97 .+-. 0.57 220
##STR00759## 840.95 C42H48N8O9S 33.10 .+-. 4.07 221 ##STR00760##
623.74 C35H41N7O4 36.10 .+-. 2.69 222 ##STR00761## 670.78
C35H38N6O6S 36.4 .+-. 2.0 223 ##STR00762## 578.66 C33H34N6O4 4.01
.+-. 0.96 224 ##STR00763## 674.74 C34H35FN6O6S 4.3 .+-. 0.7 225
##STR00764## 597.66 C32H35N7O5 4.3 .+-. 0.67 226 ##STR00765##
701.81 C41H43N5O6 4.33 .+-. 0.50 227 ##STR00766## 898.83
C42H41N6Na2O10PS 4.33 .+-. 1.59 228 ##STR00767## 580.64 4.51 .+-.
0.72 229 ##STR00768## 661.73 C32H35N7O7S 4.78 .+-. 0.69 230
##STR00769## 598.69 C34H38N4O6 4.83 .+-. 0.71 231 ##STR00770##
573.64 C30H28FN5O4S 4.85 .+-. 0.57 232 ##STR00771## 570.66
C30H30N6O4S 4.97 .+-. 0.73 233 ##STR00772## 598.65 C32H34N6O6 4.98
.+-. 0.69 234 ##STR00773## 631.14 C32H31ClN6O4S 40.2 .+-. 5.7 235
##STR00774## 675.60 C32H31BrN6O4S 40.7 .+-. 6.4 236 ##STR00775##
595.73 C35H41N5O4 41.7 .+-. 4.2 237 ##STR00776## 620.72 C33H32N8O3S
46.7 .+-. 6.13 238 ##STR00777## 620.74 C32H37FN6O4S 49.8 .+-. 4.8
239 ##STR00778## 634.72 C36H38N6O5 5.09 .+-. 1.32 240 ##STR00779##
610.70 C34H38N6O5 5.41 .+-. 0.89 241 ##STR00780## 919.25
C41H38ClN6Na2O10PS 5.50 .+-. 2.4 242 ##STR00781## 722.63
C34H37N4Na2O9P 5.80 .+-. 0.99 243 ##STR00782## 633.72 C31H35N7O6S
5.81 .+-. 0.58 244 ##STR00783## 628.63 C32H32N6O8 5.98 .+-. 1.03
245 ##STR00784## 628.72 C33H33FN6O4S 6.19 .+-. 0.73 246
##STR00785## 688.83 6.59 .+-. 0.86 247 ##STR00786## 597.70
C34H39N5O5 6.66 .+-. 0.88 248 ##STR00787## 632.71 C36H36N6O5 6.71
.+-. 1.57
249 ##STR00788## 583.68 C33H37N5O5 6.8 .+-. 1.5 250 ##STR00789##
652.77 6.98 .+-. 1.45 251 ##STR00790## 618.63 C32H32F2N6O5 1.14
.+-. 0.07 252 ##STR00791## 679.74 C38H38FN5O6 7.05 .+-. 0.87 253
##STR00792## 608.69 C34H36N6O5 7.10 .+-. 0.99 254 ##STR00793##
599.64 7.13 .+-. 1.35 255 ##STR00794## 639.70 C33H3OFN7O4S 7.17
.+-. 1.33 256 ##STR00795## 626.70 C34H38N6O6 7.20 .+-. 1.06 257
##STR00796## 641.72 C37H35N7O4 7.26 .+-. 1.30 258 ##STR00797##
641.67 C33H35N707 7.51 .+-. 2.1 259 ##STR00798## 600.63 7.62 .+-.
1.89 260 ##STR00799## 648.71 C35H36N8O5 8.43 .+-. 2.07 261
##STR00800## 694.80 C37H38N6O6S 8.48 .+-. 0.90 262 ##STR00801##
600.66 C32H36N6O6 8.48 .+-. 1.37 263 ##STR00802## 627.71
C33H33N5O6S 9.09 .+-. 0.67 264 ##STR00803## 556.62 C29H32N8O4 9.11
.+-. 1.82 265 ##STR00804## 598.65 C32H34N6O6 9.3 .+-. 0.53 266
##STR00805## 857.78 C39H38N7Na2O9PS 9.43 .+-. 1.65 267 ##STR00806##
636.70 C34H36N8O5 6.63 .+-. 1.35
[0477] It has been found according to the present invention that
compounds of general Formula (I) have less CYP3A4 inhibitory
activity (higher IC50). The details of the less measurement of
CYP3A4 inhibitory activity are disclosed in Example 1. Less CYP3A4
inhibitory activity means that the compounds of the present
invention are more pharmacologically favorable in terms of adverse
reactions.
[0478] Table 4 below shows compounds for bioactivity test selected
from the library of the present invention and IC50 values thereof,
which were measured by the P450 CYP3A4 Inhibitory Activity
Screening as described in Example 1.
TABLE-US-00004 TABLE 4 IC50(.mu.M) MEASURED BY P450 CYP3A4
INHIBITORY ACTIVITY SCREENING OF SELECTED LIBRARY COMPOUNDS CYP3A4
inhibition, M.W. IC50 (.mu.M) NO Structure Formula fluorescent
assay 1 ##STR00807## 636.74 C36H40N6O5 5.00 2 ##STR00808## 596.68
C33H36N6O5 5.23 3 ##STR00809## 619.51 C30H31BrN6O4 5.33 4
##STR00810## 618.69 C34H34N8O4 5.40 5 ##STR00811## 632.71
C36H36N6O5 5.84 6 ##STR00812## 694.80 C37H38N6O6S 6.78 7
##STR00813## 692.85 C39H48N8O4 6.84 8 ##STR00814## 661.73
C32H35N7O7S 6.95 9 ##STR00815## 607.66 C34H33N5O6 6.95 10
##STR00816## 632.71 C36H36N6O5 7.02 11 ##STR00817## 597.66
C33H35N5O6 7.58 12 ##STR00818## 636.74 C36H40N6O5 7.65 13
##STR00819## 596.68 C33H36N6O5 8.00 14 ##STR00820## 621.73
C35H39N7O4 8.42 15 ##STR00821## 581.66 C33H35N5O5 8.79 16
##STR00822## 701.79 C35H39N7O7S 9.00 17 ##STR00823## 666.77
C37H42N6O6 9.02 18 ##STR00824## 632.73 C32H36N6O6S 9.16 19
##STR00825## 564.63 C32H32N6O4 9.65 20 ##STR00826## 652.74
C36H40N6O6 10.10 21 ##STR00827## 626.7 C34H38N6O6 10.20 22
##STR00828## 610.70 C34H38N6O5 11.60 23 ##STR00829## 673.74
C32H35N9O6S 12.00 24 ##STR00830## 659.73 C38H37N5O6 12.90 25
##STR00831## 597.66 C32H35N7O5 13.10 26 ##STR00832## 607.66
C32H33N9O4 13.50 27 ##STR00833## 640.69 C33H36N8O6 16.80 28
##STR00834## 596.68 C33H36N6O5 17.90 29 ##STR00835## 487.55
C27H29N5O4 18.10 30 ##STR00836## 617.72 C32H35N5O6S 18.70 31
##STR00837## 612.68 C33H36N6O6 18.90 32 ##STR00838## 641.72
C34H39N7O6 19.90 33 ##STR00839## 612.68 C33H36N6O6 24.20 34
##STR00840## 618.7 C31H34N6O6S 24.50 35 ##STR00841## 676.74
C32H36N8O7S 26.40 36 ##STR00842## 595.71 C33H33N5O4S 26.7 37
##STR00843## 597.66 C32H35N7O5 34.30 38 ##STR00844## 640.73
C35H40N6O6 34.60 39 ##STR00845## 611.69 C33H37N7O5 35.30 40
##STR00846## 567.64 C31H33N7O4 39.10 41 ##STR00847## 612.68
C33H36N6O6 41.40Q 42 ##STR00848## 626.70 C34H38N6O6 44.10 43
##STR00849## 627.65 C32H33N7O7 44.40 44 ##STR00850## 583.64
C31H33N7O5 45.10 45 ##STR00851## 661.67 C34H34F3N7O4 >10 46
##STR00852## 623.7 C34H37N7O5 >50 47 ##STR00853## 594.66
C32H34N8O4 >50 48 ##STR00854## 567.64 C32H33N5O5 >50 49
##STR00855## 633.69 C36H35N5O6 >50 50 ##STR00856## 652.52
C32H31Cl2N5O6 >50 51 ##STR00857## 756.71 C37H38N6Na2O9 >50 52
##STR00858## 583.64 C31H33N7O5 >50 53 ##STR00859## 582.65
C32H34N6O5 >50 54 ##STR00860## 583.63 C32H33N5O6 >50 55
##STR00861## 662.71 C32H34N6O8S >50 56 ##STR00862## 584.62
C31H32N6O6 >50 57 ##STR00863## 633.63 C32H36N5O7P >50 58
##STR00864## 636.70 C34H36N8O5 >50 59 ##STR00865## 794.92
C45H42N6O6S 2.63 60 ##STR00866## 620.70 C35H36N6O5 4.84 61
##STR00867## 646.73 C37H38N6O5 5.92
[0479] The present invention is also related to methods for
preventing or treating an acute myeloid leukemia comprising
administering to the subject the compound having Formula (I)
above.
[0480] In one aspect, the present invention provides compounds that
inhibit the formation of a complex of .beta.-catenin, p300 and TCF
binding onto c-Myc protein and formation of a complex of
.beta.-catenin, p300 and TCF binding onto survivin promoter.
[0481] In another aspect, the present invention provides compounds,
in particular those having Formula (II), that control c-Myc
protein.
[0482] It has been found according to the present invention that
compounds of general Formula (I) affect the cell proliferation and
inhibit the growth of AML cancer cells, as described in Example
3.
[0483] GI50 of MV-4-11 shows cell growth inhibition activity
against AML cancer cells. The lower GI50 value means the higher
inhibition activity. A compound can be classified as active if GI50
is 10 .mu.M or below. When GI50 is 5.about.10 .mu.M, the compound
can be a candidate for a pharmaceutical. A compound is deemed
strong if GI50 is 1.about.5 and a compound is deemed very strong if
GI 50 is 1 uM or below.
[0484] Most of the compounds of the present invention showed GI50
of 5 .mu.M or below, that means they have strong inhibition
activity against AML cancer cells.
[0485] Table 5 below shows compounds for bioactivity test selected
from the library of the present invention and GI50 values thereof,
which were measured by Cell Growth Inhibition Assay) as described
in Example 3.
TABLE-US-00005 TABLE 5 CELL GROWTH INHIBITION ACTIVITY (GI50) ON
AML CANCER CELLS OF SELECTED LIBRARY COMPOUNDS NO Structure
MV-4-11, GI50 (.mu.M) 1 ##STR00868## 0.19 2 ##STR00869## 0.6 3
##STR00870## 0.18 4 ##STR00871## 0.17 5 ##STR00872## 0.05 6
##STR00873## 0.04 7 ##STR00874## 0.27 8 ##STR00875## 0.05 9
##STR00876## 0.07 10 ##STR00877## 1.32 11 ##STR00878## 1.97 12
##STR00879## 2.99 13 ##STR00880## 2.01 14 ##STR00881## 0.16 15
##STR00882## 2.14 16 ##STR00883## 0.63 17 ##STR00884## 0.36 18
##STR00885## 0.36 19 ##STR00886## 0.45 20 ##STR00887## 2.24 21
##STR00888## 0.3 22 ##STR00889## 0.74 23 ##STR00890## 0.96 24
##STR00891## 2.03 25 ##STR00892## 0.24 26 ##STR00893## 0.78 27
##STR00894## 1.11 28 ##STR00895## 1.35 29 ##STR00896## 0.39 30
##STR00897## 0.82 31 ##STR00898## 5.75 32 ##STR00899## N.D upto 50
uM 33 ##STR00900## 0.65 34 ##STR00901## 1.25 35 ##STR00902## 1.12
36 ##STR00903## 0.9 37 ##STR00904## 0.24 38 ##STR00905## 0.18 39
##STR00906## 0.96 40 ##STR00907## 0.27 41 ##STR00908## 1.56 42
##STR00909## 0.64 43 ##STR00910## 0.31 44 ##STR00911## 0.55 45
##STR00912## 2.79
[0486] The following non-limiting examples illustrate the
compounds, and the use of this invention.
Preparation Example 1,
Preparation of (N-Fmoc-N'--R.sub.4-hydrazino)-acetic acid
##STR00913##
[0488] (1) Preparation of N-Fmoc-N'-Methyl Hydrazine
##STR00914##
[0489] 2 L, two-neck, round-bottomed-flask was fitted with a glass
stopper and a calcium tube. A solution of R.sub.4-hydrazine (20 g,
139 mmol, where R.sub.4 is methyl) in THF (300 mL) was added and a
solution of DiBoc (33 g, 153 mmol) in THF was added. Saturated
sodium bicarbonate aqueous solution (500 mL) was added dropwise via
addition funnel over 2 hours with vigorous stirring. After 6 hours,
a solution of Fmoc-Cl (39 g, 153 mmol) in THF was added slowly. The
resulting suspension was stirred for 6 hours at 0.degree. C. The
mixture was extracted with ethyl acetate (EA, 500 mL) and the
organic layer was retained. The solution was dried with sodium
sulfate and evaporated in vacuo. The next step proceeded without
purification.
[0490] A 1 L, two-necked, round-bottom-flask was fitted with a
glass stopper and a calcium tube. A solution of the product from
the previous step in MeOH (300 mL) was added and conc. HCl (30 mL,
12 N) was added slowly via addition funnel with magnetic stirring
in ice water bath and stirred overnight. The mixture was extracted
with EA (1000 mL) and the organic layer was retained. The solution
was dried with sodium sulfate and evaporated in vacuo. The residue
was purified by recrystallization with n-hexane and EA to give
N-Fmoc-N'-methyl hydrazine (32.2 g, 83%). .sup.1HNMR (DMSO-D6)
.delta. 7.90.about.7.88 (d, j=6 Hz, 2H,), .delta. 7.73.about.7.70
(d, J=9 Hz, 2H,), 7.44.about.7.31 (m, 4H), 4.52.about.4.50 (d, J=6
Hz, 2H), 4.31.about.4.26 (t, J=6 Hz, 1H), 2.69 (s, 1H).
[0491] (2) Preparation of (N-Fmoc-N'--R.sub.4-hydrazino)-acetic
acid t-butyl ester
##STR00915##
[0492] 1 L, two-necked, round-bottom-flask was fitted with a glass
stopper and reflux condenser connected to a calcium tube. A
solution of N-Fmoc-N'--R.sub.4 hydrazine (20 g, 75 mmol) in toluene
(300 mL) was added. A solution of t-butylbromo acetate (22 g, 111
mmol) in toluene (50 mL) was added slowly. Cs.sub.2CO.sub.3 (49 g,
149 mmol) was added slowly. NaI (11 g, 74 mmol) was added slowly
with vigorous stirring. The reaction mixture was stirred at reflux
temperature over 1 day. The product mixture was filtered and
extracted with EA (500 mL). The solution was dried over sodium
sulfate and evaporated in vacuo. The product was purified by
chromatography with hexane: EA=2:1 solution to give
(N-Fmoc-N'-methyl-hydrazino)-acetic acid t-butyl ester (19.8 g,
70%). .sup.1H-NMR (CDCl.sub.3-d) .delta. 7.78.about.7.75 (d, J=9
Hz, 2H,), .delta. 7.61.about.7.59 (d, J=6 Hz, 2H,), 7.43.about.7.26
(m, 4H), 4.42.about.4.40 (d, J=6 Hz, 2H), 4.23 (b, 1H), 3.57 (s,
2H), 2.78 (s, 3H), 1.50 (s, 9H).
[0493] (3) Preparation of (N-Fmoc-N'-methyl-hydrazino)-acetic
acid
##STR00916##
[0494] 1 L, two-neck, round-bottomed-flask was fitted with a glass
stopper and reflux condenser connected to a calcium tube.
(N-Fmoc-N'--R.sub.4-hydrazino)-acetic acid t-butyl ester (20 g, 52
mmol) was added. A solution of HCl (150 mL, 4 M solution in
dioxane) was added slowly with vigorous stirring in an ice water
bath. The reaction mixture was stirred at RT over 1 day. The
solution was concentrated completely under reduced pressure at
40.degree. C. A saturated aq. NaHCO.sub.3 solution (100 mL) was
added and the aqueous layer was washed with diethyl ether (100 mL).
Conc. HCl was added dropwise slowly at 0.degree. C. (pH 2-3). The
mixture was extracted and the organic layer was retained (500 mL,
MC). The solution was dried with sodium sulfate and evaporated in
vacuo. The residue was purified by recrystallization with n-hexane
and ethyl acetate to give (N-Fmoc-N'-methyl-hydrazino)-acetic acid
(12 g, 72%). .sup.1H-NMR (DMSO-d.sub.6) .delta. 12.38 (s, 1H), 8.56
(b, 1H), 7.89.about.7.86 (d, J=9 Hz, 2H,), 7.70.about.7.67 (d, J=9
Hz, 2H,), 7.43.about.7.29 (m, 4H), 4.29.about.4.27 (d, J=6 Hz, 2H),
4.25.about.4.20 (t, J=6 Hz, 1H), 3.47 (s, 2H), 2.56 (s, 3H).
PREPARATION EXAMPLE 2
Title Compound
##STR00917##
[0496] To prepare the title compound, the General Scheme of
Reverse-Turn Mimetic Library which is described in the above in
this specification has been performed by the following scheme:
##STR00918##
[0497] In the above scheme `Pol` represents a bromoacetal resin
(Advanced ChemTech) and detailed procedure is illustrated
below.
[0498] Step 1
[0499] A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of
2-(4-(aminomethyl)-1H-benzo[d]imidazol-1-yl)acetamide in DMSO (1.4
mL) were placed in a Robbins block (FlexChem) having 96 well
plates. The reaction mixture was shaken at 60.degree. C. using a
rotating oven [Robbins Scientific] for 12 hours. The resin was
washed with DMF, MeOH, and then DCM
[0500] Step 2
[0501] A solution of commercial available Fmoc-Tyr(OtBu)-OH (4
equiv.), PyBob (4 equiv.), HOAt (4 equiv.), and DIEA (12 equiv.) in
DMF was added to the resin. After the reaction mixture was shaken
for 12 hours at room temperature, the resin was washed with DMF,
MeOH, and then DCM.
[0502] Step 3
[0503] To the resin swollen by DMF before reaction was added 25%
piperidine in DMF and the reaction mixture was shaken for 30 min at
room temperature. This deprotection step was repeated again and the
resin was washed with DMF, Methanol, and then DCM. A solution of
hydrazine acid (4 equiv.), HOBt (4 equiv.), and DIC (4 equiv.) in
DMF was added to the resin and the reaction mixture was shaken for
12 hours at room temperature. The resin was washed with DMF, MeOH,
and then DCM.
[0504] Step 4
[0505] The resin obtained in Step 3 was treated with formic acid
(1.2 mL each well) for 18 hours at room temperature. After the
resin was removed by filtration, the filtrate was condensed under a
reduced pressure using SpeedVac [SAVANT] to give the product as
oil. The product was diluted with 50% water/acetonitrile and then
lyophilized after freezing. .sup.1H NMR (CDCl.sub.3): .delta. 7.610
(s, 1H), 7.321.about.7.220 (m, 5H), 7.132.about.7.117 (d, J=7.4 Hz,
2H), 6.878 (s, 1H), 6.685.about.6.662 J=5.6 Hz, 1H),
6.635.about.6.619 (d, J=7.9 Hz, 2H), 6.328.about.6.313 (d, J=7.9
Hz, 2H), 6.223 (s, 1H), 5.698.about.5.619 (td, J=16.7 Hz, J=6.3 Hz,
1H), 5.391.about.5.363 (d, J=14.2 Hz, 1H), 5.211.about.5.154 (m,
3H), 4.543 (s, 2H), 4.455.about.4.427 (d, J=14.3 Hz, 1H),
4.262.about.4.153 (qd, J=15.3 Hz, J=6.1 Hz, 2H), 3.912.about.3.894
(d, J=9.0 Hz, 1H), 6.635.about.6.619 (t, J=11.0 Hz, 1H),
3.486.about.3.345 (m, 4H), 3.201.about.3.345 (dd, J=5.3 Hz, J=13.3
Hz, 1H).
Preparation Example 3
Title Compound
##STR00919##
[0507] To prepare the title compound, the General Scheme of
Reverse-Turn Mimetic Library which is described in the above in
this specification has been performed by the following scheme:
##STR00920##
[0508] In the above scheme `Pol` represents a bromoacetal resin
(Advanced ChemTech) and detailed procedure is illustrated
below.
[0509] Step 1
[0510] A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of
6-(aminomethyl)picolinamide in DMSO (1.4 mL) were placed in a
Robbins block (FlexChem) having 96 well plates. The reaction
mixture was shaken at 60.degree. C. using a rotating oven [Robbins
Scientific] for 12 hours. The resin was washed with DMF, MeOH, and
then DCM
[0511] Step 2
[0512] A solution of commercial available Fmoc-Tyr(OtBu)-OH (4
equiv.), PyBob (4 equiv), HOAt (4 equiv), and DIEA (12 equiv) in
DMF was added to the resin. After the reaction mixture was shaken
for 12 hours at room temperature, the resin was washed with DMF,
MeOH, and then DCM.
[0513] Step 3
[0514] To the resin swollen by DMF before reaction was added 25%
piperidine in DMF and the reaction mixture was shaken for 30 min at
room temperature. This deprotection step was repeated again and the
resin was washed with DMF, Methanol, and then DCM. A solution of
hydrazine acid (4 equiv), HOBt (4 equiv), and DIC (4 equiv) in DMF
was added to the resin and the reaction mixture was shaken for 12
hours at room temperature. The resin was washed with DMF, MeOH, and
then DCM.
[0515] Step 4
[0516] The resin obtained in Step 3 was treated with formic acid
(1.2 mL each well) for 18 hours at room temperature. After the
resin was removed by filtration, the filtrate was condensed under a
reduced pressure using SpeedVac [SAVANT] to give the product as
oil. The product was diluted with 50% water/acetonitrile and then
lyophilized after freezing.
[0517] .sup.1H NMR (CDCl.sub.3): .delta. 8.190.about.8.165 (d,
J=7.5 Hz, 1H), 8.055 (m, 1H), 7.900.about.7.849 (t, J=7.5 Hz, 1H),
7.472.about.7.447 (d, J=7.5 Hz, 1H), 7.397.about.7.372 (d, J=7.5
Hz, 1H), 7.335.about.7.311 (d, 7.5 Hz, 1H), 7.271.about.7.247 (m,
4H), 6.636.about.6.596 (t, J=6.0 Hz, 1H), 6.575.about.6.547 (d,
J=8.4 Hz, 2H), 6.477.about.6449 (d, J=8.4 Hz, 2H), 5.897 (m, 1H),
5.724.about.5.666 (m, 1H), 5.264.about.5.145 (m, 4H),
4.973.about.4.926 (dd, J=3.6, 10.5 Hz, 1H), 4.46.about.4.39 (dd,
J=6.0 Hz, 1H), 4.34.about.4.27 (dd, J=6.0 Hz, 1H),
4.030.about.4.021 (d, J=3.6 Hz, 1H), 3.996.about.3.928 (m, 1H),
3.778.about.3.705 (t, J=11.1 Hz, 1H), 3.705.about.3.383 (m, 5H),
3.302.about.3.238 (dd, J=5.4, 13.5 Hz, 1H)
Preparation Example 4
Title Compound
##STR00921##
[0519] To prepare the title compound, the General Scheme of
Reverse-Turn Mimetic Library which is described in the above in
this specification has been performed by the following scheme:
##STR00922##
[0520] In the above scheme `Pol` represents a bromoacetal resin
(Advanced ChemTech) and detailed procedure is illustrated
below.
[0521] Step 1
[0522] A bromoacetal resin (37 mg, 0.98 mmol/g) and a solution of
3-(aminomethyl)benzamide in DMSO (1.4 mL) were placed in a Robbins
block (FlexChem) having 96 well plates. The reaction mixture was
shaken at 60.degree. C. using a rotating oven [Robbins Scientific]
for 12 hours. The resin was washed with DMF, MeOH, and then DCM
[0523] Step 2
[0524] A solution of commercial available Fmoc-Tyr(OtBu)-OH (4
equiv.), PyBob (4 equiv.), HOAt (4 equiv.), and DIEA (12 equiv.) in
DMF was added to the resin. After the reaction mixture was shaken
for 12 hours at room temperature, the resin was washed with DMF,
MeOH, and then DCM.
[0525] Step 3
[0526] To the resin swollen by DMF before reaction was added 25%
piperidine in DMF and the reaction mixture was shaken for 30 min at
room temperature. This deprotection step was repeated again and the
resin was washed with DMF, Methanol, and then DCM. A solution of
hydrazine acid (4 equiv.), HOBt (4 equiv.), and DIC (4 equiv.) in
DMF was added to the resin and the reaction mixture was shaken for
12 hours at room temperature. The resin was washed with DMF, MeOH,
and then DCM.
[0527] Step 4
[0528] The resin obtained in Step 3 was treated with formic acid
(1.2 mL each well) for 18 hours at room temperature. After the
resin was removed by filtration, the filtrate was condensed under a
reduced pressure using SpeedVac [SAVANT] to give the product as
oil. The product was diluted with 50% water/acetonitrile and then
lyophilized after freezing.
[0529] .sup.1H NMR (CDCl.sub.3): .delta. 8.506 (s, 1H), .delta.
7.821.about.7.796 (d, J=7.6 Hz, 1H), .delta. 7.604 (s, 1H), .delta.
7.469.about.7.379 (m, 3H), .delta. 7.346.about.7.320 (m, 2H),
.delta. 7.234.about.7.210 (d, J=6.9 Hz, 2H), .delta. 7.010 (s, 1H),
.delta. 6.916.about.6.888 (d, J=8.5 Hz, 3H), .delta.
6.766.about.6.737 (d, J=8.5 Hz, 2H), .delta. 6.570.about.6.530 (t,
J=6.0 Hz, 1H), 5.810.about.5.755 (d, J=16.6 Hz, 1H), .delta.
5.715.about.5.581 (m, 1H), .delta. 5.213.about.5.163 (m, 3H),
.delta. 4.873.about.4.832 (dd, J=6.5 Hz, J=6.5 Hz, 1H), .delta.
3.892.about.3.837 (d, J=16.6 Hz, 1H), .delta. 3.633.about.3.576 (d,
J=17.2 Hz, 2H), .delta. 3.504.about.3.283 (m, 6H)
Example 1
P450 CYP3A4 Inhibitory Activity Screening
[0530] Test Compounds:
##STR00923##
[0531] Assay was conducted in a 200 .mu.L volume in 96-well
microtiter plates using cDNA-expressed human hepatic CYP3A4
(supersome, BD Gentest.TM. #456202).
7-Benzyloxy-4-trifluoromethyl-coumarin (BFC) was used as a
substrate for CYP3A4. Test articles and substrate BFC were
dissolved in 100% acetonitrile. The final volume of acetonitrile in
the incubation mixture was less than 1% (volume/volume). Potassium
phosphate buffer (pH 7.4, final concentration 0.1 M), MgCl.sub.2
(final concentration 8.3 mM), EDTA (final concentration 1.67 mM), a
test article stock solution, a CYP3A4 supersome and NADPH (final
concentration 0.25 mM) were added to each well. The reaction was
initiated by the addition of substrate (BFC, final concentration 30
M) after a 10 min pre-incubation at 37.degree. C. After 10 min
incubation at 37.degree. C., the reaction was terminated by the
addition of 75 .mu.L of acetonitrile:0.5 M Tris-base=4:1
(volume/volume). Thereafter, Fluorescent signal was measured using
a fluorometer. BFC metabolite,
7-hydroxy-4-trifluoromethyl-coumarin, was measured using an
excitation wavelength of 409 nm and an emission wavelength of 530
nm. FIGS. 2A to 2E show IC50 of the test compounds of CYP3A4
inhibition assay. Compounds A to E showed weak inhibition of CYP3A4
enzyme.
TABLE-US-00006 TABLE 6 IC.sub.50 values of Compounds against CYP3A4
activity Test Compound IC.sub.50 (.mu.M) A 13.1 B 34.6 C 24.2 D
10.2 E >10
Example 2
TopFlash Reporter Gene Bioassay for the Measurement of IC50 Against
SW480 Cells
[0532] Test Compound:
##STR00924##
[0533] SW480 cells were transfected with the usage of Superfect.TM.
transfect reagent (Qiagen, 301307). Cells were trypsinized briefly
1 day before transfection and plated on 6 well plate
(5.times.10.sup.5 cells/well) so that they were 50-80% confluent on
the day of transfection.
[0534] Four microgram (TopFlash) and one microgram (pRL-null) of
DNAs were diluted in 150 .mu.l of serum-free medium, and 30 .mu.l
of Superfect.TM. transfect reagent was added. The DNA-Superfect
mixture was incubated at room temperature for 15 min, and then, 1
ml of 10% FBS DMEM was added to this complex for an additional 3
hours of incubation. While complexes were forming, cells were
washed with PBS twice without antibiotics.
[0535] The DNA-Superfect.TM. transfect reagent complexes were
applied to the cells before incubating at 37.degree. C. at 5%
CO.sub.2 for 3 hours. After incubation, recovery medium with 10%
FBS was added to bring the final volume to 1.18 ml. After 3 hours
incubation, the cells were harvested and reseeded to a 96 well
plate (3.times.10.sup.4 cells/well). After overnight incubation at
37.degree. C. at 5% CO.sub.2, the cells were treated with Compound
F for 24 hours.
[0536] Finally, the activity was checked by means of luciferase
assay (Promega, E1960).
[0537] FIG. 3 illustrates the results of the measurement of
IC.sub.50 of Compound F for SW480 cells. IC50 was 0.73.+-.0.08
.mu.M.
Example 3
Cell Growth Inhibition Activity on AML Cancer Cells (Cell Growth
Inhibition Assay)
[0538] Test Compound:
##STR00925##
[0539] Cell growth Inhibition assay was performed to investigate
the rate of inhibition of cell proliferation by the test compounds.
MV-4-11 (human, Acute Myeloid Leukemia cell line) cells were
cultured in Iscove's modified Dulbecco's medium (IMDM) including
10% fetal bovine serum (FBS), 1.times. penicillin/streptomycin
(10,000 units/ml Penicillin, 10,000 g/ml Streptomycin in 0.85%
NaCl). MV-4-11 cells were harvested with IMDM medium and
5.times.10.sup.4 cells/well were transferred to each well of 96
well culture plates (Nunc, #167008). The test compounds were
treated with the serial dilution and duplicated for each
concentration. For the serial dilution, the test compounds were
repeatedly diluted with the same volume of media onto 96-well assay
block (costar, #3956). After the dilution, each compound was added
to each well. The background absorbance was also measured during
the test compounds treatment by adding the IMDM media in
replacement of test compound to the negative control plate. The
plates were incubated for 3 days (72 hours) at 37.degree. C. in the
humidified incubator containing 5% CO.sub.2. On the last day, 20
.mu.L of CellTiter 96 Aqueous One Solution (Promega #G3581) was
added to the culture in each well and the plates were incubated for
a few hours at 37.degree. C. in the humidified incubator containing
5% CO.sub.2. After the incubation, the absorbance of each cell was
measured at 490 nm using an EnVision (Perkinelmer, USA). The GI50
values were calculated using a Prism 3.0 program. The results
showed that the test compounds affected the cell proliferation and
inhibited the growth of AML cancer cells. FIG. 4 shows the result
of the inhibition. GI50 of Compound B was 0.188 .mu.M.
[0540] As described above, the present invention provides new
compounds of revers-turn mimetics, which can be used as
pharmaceutical compounds, especially on AML cancer cells. The
invention has been described in detail with reference to preferred
embodiments thereof. However, it will be appreciated by those
skilled in the art that changes may be made in these embodiments
without departing from the principles and spirit of the invention,
the scope of which is defined in the appended claims and their
equivalents.
* * * * *